List of cocaine analogues

Cocaine with its numerical substitution position locants.
2′ (6′) = ortho, 3′ (5′) = meta & 4′ = para

This is a list of cocaine analogues. A cocaine analogue is a (usually) artificial construct of a novel chemical compound from (often the starting point of natural) cocaine's molecular structure, with the result product sufficiently similar to cocaine to display similarity in, but alteration to, its chemical function. Within the scope of analogous compounds created from the structure of cocaine, so named "cocaine analogues" retain 3β-benzoyloxy or similar functionality (the term specifically used usually distinguishes from phenyltropanes, but in the broad sense generally, as a category, includes them) on a tropane skeleton, as compared to other stimulants of the kind. Many of the semi-synthetic cocaine analogues proper which have been made & studied have consisted of among the nine following classes of compounds:^{[lower-alpha 1]}

• stereoisomers of cocaine
• 3β-phenyl ring substituted analogues
• 2β-substituted analogues
• N-modified analogues of cocaine
• 3β-carbamoyl analogues
• 3β-alkyl-3-benzyl tropanes
• 6/7-substituted cocaines
• 6-alkyl-3-benzyl tropanes
• piperidine homologues of cocaine

Above: Cocaine in the chair conformation of the tropane-ring, with only its tropane locants given.

Below: Alternate two-dimensional molecular diagram of cocaine; shown specifically as a protonated, NH+, hydrochloride, and disregarding 3D stereochemistry

However strict analogues of cocaine would also include such other potential combinations as phenacyltropanes & other carbon branched replacements not listed above. The term may also be loosely used to refer to drugs manufactured from cocaine or having their basis as a total synthesis of cocaine, but modified to alter their effect & QSAR. These include both intracellular sodium channel blocker anesthetics and stimulant dopamine reuptake inhibitor ligands (such as certain, namely tropane-bridged-excised, piperidines). Additionally, researchers have supported combinatorial approaches for taking the most promising analogues currently elucidated and mixing them to the end of discovering novel & efficacious compounds to optimize their utilization for differing distinct specified purposes.^{[lower-alpha 2]}

Two dimensional schematic drawing of cocaine's structural dynamic interaction points with dopamine transporter binding sites.

Although the carbmethoxy is denoted in its function as a hydrogen bond in this depiction, it has been found that it is primarily eletrostatic factors which dominate binding within this space of the molecular surface area over the operative principle of hydrogen bonding.^{[lower-alpha 3]}

Two out of three potential "reverse esters" of cocaine (the third one being a single "di-substituted" structure with both the 'methyl ester' & 'benzoate' reversed in tandem)

Analogs sensu stricto

Cocaine Stereoisomers

There are eight stereoisomers of cocaine (with the internal portion of the tropane ring unchanged).^{[lower-alpha 4]} Not counting mesomers but including the one & five to eight position bond bridge of the tropane system having R- & S- configurations potentially, containing four asymmetric carbons, cocaine can be counted as having as many as sixteen stereoisomers. However geometric constraints imparted by the bridgehead amine allow only eight to be created.

Where the 2D diagrams given for the structural analogs below do not indicate stereochemistry, it should be assumed they share the conformation of R-cocaine, unless noted otherwise.

The natural isomerism of cocaine is unstable in several ways besides having a high degree of lability; for instance: the C2 carbmethoxy in its biosynthesis end-product maintains the axial position, which can undergo epimerization via saponification to obtain the former in an equatorial position.

The creation of the following analogues of cocaine have traditionally required a step which has utilized 2-CMT as an intermediate molecular product.

Benzoyl branch cleavage substitutions (excluding the exhaustive phenyl group)

Salicylmethylecgonine[3]	Methylvanillylecgonine[4][5]

N.B. Fries rearrangement product of aspirin used to make salbutamol. It is relevant to the precursor here though because the migrated acetyl group can be the subject of a haloform reaction. A more direct route to vanillic acid though is just oxidation of the vanillin to a functionalized benzoic acid.

Arene benzene-ring 2′, 3′, 4′ (5′ & 6′) position (aryl) substitutions

para-substituted benzoylmethylecgonines

Carbon 4′-hydrogen Substitutions (benzene-4′ "para" substituted benzoyloxytropanes)^{[lower-alpha 5]
Data-set congruent to, and aggregate with, following tables
IC₅₀ values}

Structure	S. Singh's alphanumeric assignation (name)	4′=R	DAT [3H]WIN 35428	5-HTT [3H]Paroxetine	NET [3H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	(cocaine)	H	249 ± 37	615 ± 120	2500 ± 70	2.5	10.0
non-benzoyloxy analogue comparative ligands non-tropane analogue comparative ligands	11b (WIN 35428) (nisoxetine) (fluoxetine)	F — —	24 ± 4 775 ± 20 5200 ± 1270	690 ± 14 762 ± 90 15 ± 3	258 ± 40 135 ± 21 963 ± 158	28.7 1.0 0.003	10.7 0.2 0.2
	183a	I	2522 ± 4	1052 ± 23	18458 ± 1073	0.4	7.3
	183b	Ph	486 ± 63	-	-	-	-
	183c	OAc	144 ± 2	-	-	-	-
	183d	OH	158 ± 8	3104 ± 148	601 ± 11	19.6	3.8
	(4′-Fluorococaine)[6]	F	-	-	-	-	-
	(para-Isothiocyanatobenzoylecgonine methyl ester)[7] (p-Isococ)	NCS	-	-	-	-	-

The MAT binding pocket analogous to the lipophilic place on cocaine-like compounds, inclusive of the benzene ring, is approximate to 9 Å in length. Which is only slightly larger than a phenyl ring by itself.^{[lower-alpha 6]}

meta-substituted benzoylmethylecgonines

Carbon 3′-hydrogen Substitutions (benzene-3′ "meta" substituted benzoyloxytropanes)^{[lower-alpha 7]
Data-set congruent to, and aggregate with, preceding and following tables
IC₅₀ values}

Structure	S. Singh's alphanumeric assignation (name)	3′=R	DAT [3H]WIN 35428	5-HTT [3H]Paroxetine	NET [3H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	184a	I	325ɑ	-	-	-	-
	184b	OH	1183 ± 115	793 ± 33	3760 ± 589	0.7	3.2
	191	OBn	-	-	-	-	-
	(m-Isococ)	NCS	-	-	-	-	-

• ^ɑIC₅₀ value for displacement of [³H]cocaine

ortho-substituted benzoylmethylecgonines

The hydroxylated 2′-OH analogue exhibited a tenfold increase in potency over cocaine.^{[lower-alpha 8]}

Carbon 2′-hydrogen Substitutions (benzene-2′ "ortho" substituted benzoyloxytropanes)^{[lower-alpha 9]
Data-set congruent to, and aggregate with, preceding and following tables
IC₅₀ values}

Structure	S. Singh's alphanumeric assignation (name)	2′=R	DAT [3H]WIN 35428	5-HTT [3H]Paroxetine	NET [3H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	185a	I	350ɑ	-	-	-	-
	185b	F	604 ± 67	1770 ± 309	1392 ± 173	2.9	2.3
	185c (2′-Acetoxycocaine)[8]	OAc	70 ± 1	219 ± 20	72 ± 9	3.1	1.0
	185d (2′-Hydroxycocaine)[3]	OH	25 ± 4	143 ± 21	48 ± 2	5.7	1.9

• ^ɑIC₅₀ value for displacement of [³H]cocaine

manifold benzoyloxy phenyl-substitutions

Multi-substitutions (substitutions of substitutions; e.g. meta- & para-) or manifold ("many-fold") substituted analogues are analogues where more than one modification from the parent molecule takes place (having numerous intermediary constituents). These are created with often surprising structure–activity relationship results extrapolated therefrom. It is even a common case where two separate substitutions can each yield a weaker, lower affinity or even wholly non-efficacious compound respectively; but due to findings that oftentimes, when used together, such two mutually inferior changes being added in tandem to one analogue has the potential to make the resultant derivative display much greater efficacy, affinity, selectivity &/or strength than even the parent compound; which otherwise was compromised by either of those two alternations when made alone.

For an exposition & allusion to this mechanism observe that the opioid oxycodone, derived from codeine, is 1.5×—1.7× the analgesic potency of morphine (an opioid to which codeine is by comparison only 8%—12% as potent relatively, or 0.17th its strength in rats); yet oxycodone's intermediates in its synthesis from codeine are: ⅓ the potency of codeine (i.e. codeinone); 0.13 that of morphine (i.e. 14-hydroxycodeine) in rats and less in mice (to illustrate: the former even being less than the 0.17 of morphine that codeine is); with the final possible stand alone intermediate compound between codeine & oxycodone (i.e. 7,8-dihydrocodeine) being at most 150% to 200% that of codeine.^[9]

Manifold Compositions of Terminating Phenyl Ring Substitutions (Multiple benzene-2′,3′ & 4′ combined substituted benzoyloxytropanes)^{[lower-alpha 10]
Data-set (excepting instanced references inside table) congruent to, and aggregate with, preceding and following tables
IC₅₀ values}

Structure	S. Singh's alphanumeric assignation (name)	ortho-2′=R	meta-3′=R	para-4′=R	DAT [3H]WIN 35428	5-HTT [3H]Paroxetine	NET [3H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	186	HO	H	I	215 ± 19	195 ± 10	1021 ± 75	0.9	4.7
	(Vanillylmethylecgonine)[4]	H	OCH3	OH	-	-	-	-	-

benzoyl phenyl-alterations

The naphthalene analogs allow for further numeric substitutions, including eight position peri substituted patterns. Many more alterations creating differing aromatic rings are possible.

Terminating Phenyl Carbon Ring Fusions & Alterations^{[lower-alpha 11]
Data-set congruent to, and aggregate with, preceding table
IC₅₀ values}

Structure	S. Singh's alphanumeric assignation (name)	C=R	DAT [3H]Cocaine (IC50)	5-HTT [3H]Paroxetine	NET [3H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	187	1-naphthalene	742 ± 48	-	-	-	-
	188	2-naphthalene	327 ± 63	-	-	-	-

Benzoyl branch modifications

Parent compound of a series of spirocyclic cocaine benzoyl linkage modification analogs created by Suzuki coupling method of ortho-substituted arylboronic acids and an enol-triflate derived from cocaine. (the carbomethoxyl group should be alpha configured, which is not specified in the above depiction)^[10]

• Benzoylthiomethylecgonine^[11]

A sulfur in place of the oxygen at the benzoyl ester single bond results in a lower electronegativity than that of cocaine.

C1-tropane-ring hydrogen substitutions

C1 substitutions^[12]
HEK-293 heterologously expressed human monoamine transporter cells for K_i values of compounds inhibiting neurotransmitter uptake.^[13]

Structure	Trivial name	R (C1 moiety)	Ki (nM) @ DAT	Ki (nM) @ SERT	Ki (nM) @ NET	σ1 affinity Ki	σ2 affinity Ki	IC50 (μM) Na+ inhibition (Vertridine-Stimulated influx of sodium channels in Neocortical neurons)c	LogP (XLogP3 algorithm, Cheng et al., 2007)
	(—)-Cocaine	H	326 ± 106	513 ± 143	358 ± 69	6.7 ± 0.3 μMd[14]	—	6.99 ± 2.43	2.30
	(—)-1-methyl-cocaine	Me	163 ± 23	435 ± 77	488 ± 101	"unappreciable"	1.13 μM	16.01 ± 1.90	2.67
	(—)-1-ethyl-cocaine	Et	95.1 ± 17.0ɑ	1,106 ± 112	598 ± 179	—	—	—	3.20
	(—)-1-propyl-cocaine	n-Pr	871 ± 205ɑ	2,949 ± 462b	796 ± 195	—	—	—	3.56
	(—)-1-pentyl-cocaine	n-C5H11	1,272 ± 199b	1,866 ± 400ɑ	1,596 ± 21b	—	—	—	4.64
	(—)-1-phenyl-cocaine	Ph	32.3 ± 5.7b	974 ± 308	1,980 ± 99b	524 nM	198 nM	0.29 ± 0.07	3.77

• ^ɑ, P < 0.05 compard with (—)-cocaine (one-way ANOVA followed by Dunnett's multiple comparisons test)
• ^b, P < 0.01 compard with (—)-cocaine (one-way ANOVA followed by Dunnett's multiple comparisons test)
• ^cLidocaine was found to have a value of 39.6 ± 2.4, the weakest of all tested.
• ^dSame reference gives 25.9 ± 2.4 μM for (+)-cocaine and 13.6 ± 1.3 μM for norcocaine. Comparably it gives 12.7 ± 1.5 μM for the sigmaergic affinity of (+)-amphetamine. Another reference gives 1.7-6.7 μM for (—)-cocaine. All values K_i.^[15]
• Using same data-set as above table, the following compounds were found to compare as:
  • CFT @ DAT = 39.2 ± 7.1 (n = 5)
  • fluoxetine @ SERT = 27.3 ± 9.2 (n = 3)
  • desipramine @ NET = 2.74 ± 0.59 (n = 3)

Cocaine analogs substituting the C1-tropane ring position, requiring sulfinimine (N-sulfinyl-imine) chemistry (before the innovation of which were untenable) which bind unlike the typical configuration at DAT (open to out) as cocaine (with its terminal D79-Y156 distance of 6.03 Å), or in the atypical (closed to out) conformation of the benztropines (3.29 Å). Though closer to the open to out: (—)-1-methyl-cocaine = 4.40 Å & (—)-1-phenyl-cocaine = 4.89 Å, and exhibiting preferential interaction with outward facing DAT conformation, they appear to have the lack of behavioral stimulation as-like the closed to out type. Despite having non-stimulant behavior profiles, they still seem to have anti-depressant behavioral profiles.^[13]

The C1 phenyl analog is ten times stronger than cocaine as a dopamine reuptake pump ligand, and twenty four times stronger as a local anesthetic (voltage-dependent Na+ channel blocker), whereas the C1 methyl analog is 2.3 times less potent as a local anesthetic.^[13]

2β-substitutions (including transesterification metabolite substitution cocaethylene)

The consideration that large, bulky C2 substituents would alter the tropane by distorting the piperidine ring part of its skeleton sufficiently enough to impair its functionality, or that in said event such would hamper binding, in particular at the 8-aza end to ease steric strain going toward its place from the 2-position,^{[lower-alpha 12]} appear to in many cases be unfounded.^{[lower-alpha 13]} (examples shown in collapsed/bundled table of images below)

Intermediate compound #203

Additional 2β-Cocaine analogue molecular structures
Compounds with greater SERT affinity than cocaine parent (slightly less @ DAT, significantly less, except for #196g, @ NET) Compounds with greater DAT affinity than cocaine parent (SERT & NET affinity untested; note however their similarity to more potent SERT ligands above) (greater)>@ DAT, (lesser)<@ SERT, (much less)<<@ NET

Compound 197b displayed a 1,131-fold increased selectivity in affinity over the serotonin transporter, with only slight reductions in potency for the dopamine & norepinephrine transporters.^{[lower-alpha 14]} Whereas 197c had a 469× increase at SERT, with greater affinity for DAT than cocaine & was approximately equipotent to NET.^{[lower-alpha 15]} 197b was 137×, and 196c 27× less potent at binding to the serotonin transporter, but both had a NET / DAT ratio that made for a better dopaminergic than cocaine.^{[lower-alpha 16]}

Direct 2β Substitutions^{[lower-alpha 17]
(IC₅₀ nM values)}

Structure	S. Singh's alphanumeric assignation (name)	R	DAT [3H]WIN 35428	5-HTT [3H]Paroxetine	NET [3H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	(Cocaine)	Me	89 ± 4.8	1045 ± 89	3298 ± 293	11.7	37.0
	196a (Cocaethylene)	Et	195 ± 45	5801 ± 493	10000 ± 751	29.7	51.3
	196b	n-Pr	196 ± 46	4517 ± 430	6124 ± 262	23.3	31.2
	196c	i-Pr	219 ± 48	25224 ± 1498	30384 ± 1685	115	139
	196d	Ph	112 ± 31	33666 ± 3330	31024 ± 1909	300	277
	196e	Bn	257 ± 14	302 ± 23	20794 ± 950	1.2	80.9
	196f	β-phenethyl	181 ± 10	615 ± 52	19944 ± 1026	3.4	110
	196g	γ-phenylpropyl	147 ± 19	374 ± 15	4893 ± 344	2.5	33.3
	196h	cinnamyl	371 ± 15	368 ± 6.3	68931 ± 3476	1.0	186
	196i	p-NO2-β-phenethyl	601 ± 28	-	-	-	-
	196j	p-Cl-β-phenethyl	271 ± 12	-	-	-	-
	196k	p-NH2-β-phenethyl	72 ± 7	-	-	-	-
	196l	p-NCS-β-phenethyl	196 ± 14	-	-	-	-
	196m	p-azido-β-phenethyl	227 ± 19	-	-	-	-
	196n	(p-NHCOCH2Br)β-phenethyl	61 ± 6	-	-	-	-
	196o	(p-NHCO(CH2)2CO2Et)β-phenethyl	86 ± 4	-	-	-	-
	197a	NH2	753 ± 41.3	13725 ± 1256	3981 ± 229	18.2	5.3
	197b	-NMe2	127 ± 6.36	143713 ± 8854	7329 ± 158	1131	57.7
	197c	-N(OMe)Me	60 ± 6.4	28162 ± 2565	3935 ± 266	469	65.6
	197d	-NHMe	2424 ± 118	44798 ± 2105	4213 ± 206	18.5	1.7
	197e (Benzoylecgonine)	-OH	195000	-	-	-	-
	197f	HOCH2-	561 ± 149	-	-	-	-
	197g (Tropacocaine)	H	5180 ± 1160	-	-	-	-

Bioisostere 2-position carbmethoxy-ester functional replacements

Benzoylecgonine, i.e. compound 197e, (differing from its cocaine parent only by de-methylation of the C2 carbmethoxy to that of a carboxy) has an extreme loss in potency (its approximate affinity being 195,000 nM) as displayed by in vitro methodologies for determining binding efficacy (wherein BBB penetration does not factor-in on the matter in the manner as in vivo studies) and is posited to be due possibly to zwitterion formation.^{[lower-alpha 18]}

2β-isoxazole and isoxazoline ring containing analogues^{[lower-alpha 19]
Data-set congruent to, and aggregate with, following tables
IC₅₀ nM values}

Structure	S. Singh's alphanumeric assignation (name)	R	[3H]Mazindol	[3H]DA	Selectivity Uptake/Binding
	(Cocaine)	(H)	580 ± 70	570 ± 180	1.0
	198a	H	520 ± 40	260 ± 70	0.5
	198b	CO2Et (5′-carboethoxy-)	120 ± 10	290 ± 40	2.4
	198c	BOC	2230 ± 220	1820 ± 810	0.8
	198d	Ph	2000 ± 640	2920 ± 1620	1.5
	198e	CH=CHCO2Me	3600 ± 400	3590 ± 1180	1.0

2-[(2-methoxy-2-oxoethoxy)methyl] cocaine analogue.^[16]

[²H₃-N-methyl]-cocaine: reagent analogue used in radio-labeling ligand binding sites.

C2-ethyl-OSO₂CF₂ cocaine analogue.^[16]

Vinylogous 2β-position carbmethoxy-ester functional replacements

201b & 201c show significant increased potency over cocaine; whereas 201a, 201d & 201e are considerably less so. This infers the hydrogen bond acceptor at the 2β position to not necessarily be of exclusive import in creation of higher binding analogues of cocaine.

[²H₅-phenyl]-cocaine: reagent analogue, as above thumbnail of similar compound: rendered from its cocaine parent by replacing a cluster of several adjacent hydrogens (from among the hydrogens that comprise the entire circumference common to every basic molecular perimeter) with deuterium, in an equivalent but localized spread or cluster.

vinylogous 2β analogues^{[lower-alpha 22]
Data-set congruent to, and aggregate with, preceding table
IC₅₀ nM values}

Structure	S. Singh's alphanumeric assignation	R	[3H]Mazindol	[3H]DA	Selectivity Uptake/Binding
	201a	H	1730 ± 550	1120 ± 390	0.6
	201b	Cl	222 ± 49	368 ± 190	1.6
	201c	CO2Et	50 ± 10	130 ± 10	2.6
	201d	CH=CHCO2Et	1220 ± 100	870 ± 50	0.7
	201e	PO(OEt)2	4850 ± 470	5500 ± 70	1.1

N-modifications

Additional N-modified cocaine analogue molecular structures

8-oxa cocaine analogs:^[17] (cf Meltzer with PTs)

Eight position carba N6 & N7 analogues.^[16]

ortho-phenyl of the moved nitrogen.^[16]

Nitrogen Substitutions
Mazindol comparison table
(^ɑβ-CFT comparison notation)^{[lower-alpha 23]}

Compound	S. Singh's alphanumeric assignation (name)	N8-R	[3H]Mazindol binding	[3H]DA uptake	Selectivity Uptake/Binding
	217 (Cocaine methiodide)	-	10700 ± 1530ɑ	-	-
	(Cocaine)	CH3	280 ± 60 102ɑ	320 ± 10	1.1
	218 (Norcocaine)	H	303 ± 59ɑ	-	-
	219a	Bn	668 ± 67ɑ	-	-
	219b	Ac	3370 ± 1080ɑ	-	-
	219c	CH2CH2OH	700 ± 100	1600 ± 200	2.3
	219d	CH2CO2CH3	480 ± 40	1600 ± 100	3.3
	219e	CH2CO2H	380 ± 20	2100 ± 400	5.5
	220a	SO2CH3 (Ms)	1290 ± 80	1970 ± 70	1.5
	220b	SO2CF3 (Tf)	330 ± 30	760 ± 20	2.3
	220c	SO2NCO	120 ± 10	160 ± 10	1.3
	220d	SO2Ph	20800 ± 3500	61000	2.9
	220e	SO2C6H4-4-NO2 (nosyl)	5720 ± 1140	18800 ± 90	3.3
	220f	SO2C6H4-4-OCH3	6820 ± 580	16400 ± 1400	2.4
	221a	NO	99500 ± 12300	231700 ± 39500	2.3
	221b	NO2	7500 ± 900	21200 ± 600	2.8
	221c	NHCOCH3	>1000000	>1000000	-
	221d	NH2	-	-	-

• ^ɑIC₅₀ (nM) for displacement of [³H]WIN 35428

Tropane fused/bridged (N-constrained/tethered) analogues

A selection of "front bridged" & "back bridged" cocaine analogs.

Derivations upon fusions of the tropane's nitrogen bridge^{[lower-alpha 24]}

Compound	S. Singh's alphanumeric assignation	R	[3H]Mazindol	[3H]DA	Selectivity Uptake/Binding
	222		44900 ± 6200	115000 ± 15700	2.6

Back-bridged cocaine analogues are considered more akin to untethered cocaine analogs & phenyltropane derivatives (where the nitrogen lone pair is not fixed or constrained) and better mimics their affinities. This is due to when the eighth carbon tropane position is freely rotatable and unbound it preferably occupies the axial position as defining its least energy & most unhindered state. In front-bridged analogs the nitrogen lone pairings rigid fixity makes it reside in an equatorial placing for the piperidine ring-part of the tropane nucleus, pointing to the two-carbon & three methylene unit bridgehead; giving the attested front-bridged cocaine analogues preference for SERT over DAT.^{[lower-alpha 25]}

Constrained thiophene tropane^[18][19] Note the pi symmetry of the partially hydrogen-unsaturated cyclopentane substitutes the benzene place with the other tricyclic tropanes to the right.

Tricyclic tropanes, values in K_i (nM)^[20]
1st structure (di-chloro benzene, 2β-CH₂OCOMe) SERT = 1.6, DAT = 1870, NET = 638
2nd structure (para-bromo, meta-chloro, 2β-CO₂Me) SERT = 2.3, DAT = 5420, NET = 459
3rd structure (para-iodo, meta-chloro, 2β-CH₂OCOPh) SERT = 0.06, DAT/NET both = >10K

Azabornane tropane ring contraction

Alterations shortening the tropane ring system while including the benzoyloxy length at the C3 have been made, contrasting the azabornane phenyltropanes;^[16] likely remedying the shallow penetration (for good efficacy) of the latter.

5-benzoatic (left) & 6-benzoatic (right)

6/7 tropane position methoxycocaine & methoxypseudococaine analogues

Phenylsulfanyl, C2-C3 unsaturated nonisomeric (C2 inclusive) C4 chloro analog.^[16]

3β-position 2′—(6′) & 2β-substitution combination analogues

4′-Iodococaine-2β-substituted analogues^{[lower-alpha 27]}

Compound	S. Singh's alphanumeric assignation	2β-R	C2′-R	IC50 (nM) (displacement of [3H]WIN 35428)
	211a	CO2OH	H	6214 ± 1269
	211b	CH2OCOCH3	H	2995 ± 223
	211c	CONHCH3	H	>100000
	211d	CO2Et	H	2031 ± 190
	211e	CO2-i-Pr	H	1377 ± 10
	211f	CO2Ph	H	2019 ± 253
	211g	CO2CH2Ph	H	4602 ± 325
	211h	3-phenyl-1,2,4-oxadiazole	H	3459 ± 60
	211i	CH=CH2	H	2165 ± 253
	211j	CH2CH3	H	2692 ± 486
	212	CO2-i-Pr	HO	663 ± 70 4507 ± 13ɑ 34838 ± 796b

• ^ɑFor displacement of [³H]paroxetine (5-HTT & NET)
• ^bFor displacement of [³H]nisoxetine (5-HTT & NET)

3β-Carbamoyl analogues

3-position carbamoyl linkage substituting benzoyloxy analogues^{[lower-alpha 28]}

Compound	S. Singh's alphanumeric assignation (name)	X	IC50 (nM) inhibition of [3H]Cocaine binding (Rat Striatal Tissue)	IC50 (nM) inhibition of [3H]DA uptake (Rat Striatal Tissue)	Selectivity uptake/binding
	(Cocaine)	(H)	70 ± 10	210 ± 70	3.0
	223a	H	5600 ± 700	52600 ± 3000	9.4
	223b	4-NO2	1090 ± 250	5700 ± 1200	5.2
	223c	4-NH2	63300 ± 12200	>100000	-
	223d	4-N3	1000 ± 240	1180 ± 360	1.2
	223e	4-NCS	260 ± 60	490 ± 80	1.9
	223f	3-NO2	37 ± 10	178 ± 23	4.8
	223g	3-NH2	2070 ± 340	23100 ± 900	11.1
	223h	3-N3	630 ± 150	3900 ± 1590	6.2
	223i	3-NCS	960 ± 210	4900 ± 420	5.1

Phenyl 3-position linkage substitutions

A 3-Dimensional (stick-&-ball) rendering of Troparil: A structural analogue of cocaine with omitted -COO- linkage – a parent compound of many MAT ligands; those of the phenyltropane class. (Here it is depicted in an unfavourable conformation of the O-Me; The methyl has to be at the other oxygen and trans to optimize its functional stimulation.)

The top image above is a 2-Dimensional emulation of the orientation for the animated 3D image to the far right, with a methoxy that is distal from the phenyl group and cis. While the alternate image below that to its bottom shown above is one with the carboxyl methyl group proximal to the phenyl, in its optimum conformation, with a likewise optimum trans configuration.

See: List of phenyltropanes (Many phenyltropanes are derived from cocaine metabolites, such as methylecgonidine, as precursors. Whereas fully synthetic methods have been devised from the starting material of vinylcarbenoids & pyrroles.)^[21]

The difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact.^{[lower-alpha 29]} This may account for PTs increased behavioral stimulation profile over cocaine.^{[lower-alpha 30]} Differences in binding potency have also been explained considering solvation effects; cocaine containing 2β,3β-ester groups being calculated as more solvated than the WIN-type compounds (i.e. troparil). Higher pK_ɑs of the tropane nitrogen (8.65 for cocaine, 9.55 for troparil & 11.95 for vinyl analogue 43a), decreased aqueous solvation & decreased conformational flexibility added to increased binding affinity.^{[lower-alpha 31]}

Despite the observation of increased stimulation, phenyltropanes lack the local anesthetic sodium channel blocking effect that the benzoyloxy imparts to cocaine. Beside topical affect, this gives cocaine an affinity for binding to sites on the dopamine and serotonin sodium dependent transport areas that are distinct & specific to MAT in contrast to the general sodium channels; creating a separate mechanism of relational affinity to the transporters in addition to its inhibition of the reuptake for those transporters; this is unique to the local anesthetic value in cocaine & analogues with a similar substitute for the benzoyloxy that leaves the sodium channel blockage ability intact. Rendering such compounds as different functionally in their relation to MAT contrasted to phenyltropane analogues which have the local anesthetic bridge removed.^[22] In addition, it even has been postulated that a crucial role regarding the electron energy imparted via voltage sensitization (and thus action potential blockage with a molecule capable of intersecting its specific channel, in the case of cocaine a sodium channel, then acting upon atomic scale triboelectric effect that potentially serves in re-quantifying its charge) upon a receptor binding site may attenuate the mediating influence of the inhibitory regulation that autoreceptors play by their slowing neurotransmitter release when an efflux is created through an instance of agonism by a compound; allowing said efflux to be continued without the body's attempt to maintain homeostasis enacting in as readily responsive a manner to its conformational change.^[23]

Various phenyltropane examples

3β-Alkylphenyltropane & 3β-Alkenyl analogues

The compound 224e, the 3β-styrene analogue, had the highest potency in its group. While 224b & 224c showed the most selectivity, with 224b having a ten-fold greater potency for the dopamine transporter than cocaine.^{[lower-alpha 32]}

3β-styrene alkylphenyl cocaine analog image showing stereochemistry.
(i.e. compound "224e")

3-position alkylphenyl linkage substituting benzoyloxy analogues^{[lower-alpha 33]}

Compound	S. Singh's alphanumeric assignation (name)	n	IC50 (nM) [3H]Cocaine binding	IC50 (nM) [3H]DA uptake	Selectivity uptake/binding
	(Cocaine)		101 ± 26	209 ± 20	2.1
	224a	1	885 ± 18	1020 ± 52	1.1
	224b	2	9.9 ± 0.33	70.5 ± 1.0	7.1
	224c	3	344 ± 12	2680 ± 190	7.8
	224d		71.6 ± 0.7	138 ± 9	1.9
	224e		2.10 ± 0.04	5.88 ± 0.09	2.8

6-Alkyl-3-benzyltropane analogues

Cocaine 229b—f series analogues

Cocaine 230b—f series analogues

Cocaine 231c—f series analogues

Cocaine 232c, d & f series analogues

Benzylidene derivatives of 6-alkyl-3-benzyltropanes^{[lower-alpha 35]}

Sub-category (S. Singh compound #)	a R=H	b R=Me	c R=Et	d R=n-Pr	e R=n-Bu	f R=Bn
6α-isomers: 237a—f
6β-isomers (exo): 238a—f
3β-benzyl derivatives: 239a—f
intermediate alkylidene esters: 240a—f

N.B. that 237a and 238a are the same compound as both are the parent for either series with a hydrogen saturated in their respective substitution place.

Direct 2,3-pyrimidino fused

above: Strobamine, a DARI functional cocaine analog with structural semblance.^[24]

below: Chalcostrobamine

cf. strobamine (at right) for a more efficacious compound as like the below.

2,3-direct fused "di-hetero-benzene" rigidified cocaine analogs.^[25]
(Binding values @ biogenic amine transporters (BATs) for rigid and semi-rigid analogs)

Structure	alphanumeric assignation	R1	R2	hDAT IC50 (nM)	hSERT IC50 (nM)	hNET IC50 (nM)
	(—)-3a	H	C6H5	58,300 (20,200)	6140 (3350)	NA
	(+)-3a	H	C6H5	48,700 (20,100)	6030 (3400)	NA
	(—)-3b	H	NH2	NA	NA	NA
	(+)-3b	H	NH2	NA	NA	NA
	(—)-3c	H	CH3	NA	NA	NA
	(+)-3c	H	CH3	NA	NA	NA
	(—)-3d	H	H	NA	NA	NA
	(+)-3d	H	H	NA	NA	NA
	(+/—)-3e	C6H5	C6H5	30,000 (11,200)	3650 (1700)	NA

• "NA" = "no affinity", e.g. unquantifiable.

Direct di-hetero-benzene (pyrimidino) 2,3-fused and thus rigidified cocaine analogs.^[25]

Piperidine cocaine-homologues

Tricyclo benzoyloxy dibenzene cocaine analogue. cf. benztropine compound #277, tropatepine, etc.^[16]

cf. phenyltropane piperidine-homologues for compounds with a more optimized conformation that yield higher affinities when binding to MAT.

Cocaine hapten analogues

"GNC", a cocaine analog designed to minimize the formation of noncocaine-like structures through its chemical coupling to the Ad proteins; all while maintaining the element of its antigenic determinant from the moiety of cocaine.^[26]

Cocaine analogs which elicit noncatalytic antibodies^{[lower-alpha 37]}

Compound	S. Singh's alphanumeric assignation (name)	2β-R
	394 (GNC)ɑ	CO2(CH2)5CO2H
	395 (Succinyl Norcocaine)[27]	CO2CH3
	GNEb[28] including carrier proteins: GNE-FLiC GNE-KLH GNE-BSA
	396	CONH(CH2)5CO2H

• ^ɑ6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carbonyloxy-hexanoic acid
• ^b6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid

Tetrahedral-intermediate cocaine-hapten compound #400

Cocaine transition state analogues (TSAs) which generate catalytic antibodies^{[lower-alpha 38]}

Compound	S. Singh's alphanumeric assignation (name)	R
	401a	CH3
	401b	(CH2)5CO2H
	401c	CH2CO2H
	401d	COCH2CH2CO2H
	401e	H
	401f	CH2CH2Br
	385g	(CH2)2NHCO(CH2)2CONH2
	402a	O(CH2)4NHCO(CH2)2CO2…2,3-dihydro-1H-isoindole-1,3-dione
	402b	OH
	402c	O(CH2)2…1,4-xylene…NH2
	402d	NH(CH2)5CO2H
	402e	O(CH2)4NHCO(CH2)2CONH2
	403a	NH2
	403b	NHCOCH2Br
	403c	NHCO(CH2)3CO2H
	403d	(CH2)3NHCO(CH2)2CONH2

Cocaine haptens that create catalytic anti-bodies require transitional states as affected in vivo.^[29][30]

Anti-idiotypic & butyl-cholinesterase mediated immunopharmacotherapy cocaine analogs^[31]

Compound	Name
	K1-KLH/BSA[32]
	K2-KLH/BSA

Structural/Functional intermediate analogues

Tropane (non-ecgonine) analogues

The first compound of those categorized as an "intermediate analog" in the series presented immediately below (para-fluoro-benzoyl-tropane), although several modifications distant from its cocaine parent structure, fits every technical criteria of a strict analog type to cocaine. It is given here, however, as the nearest relational structure along the instanced spectrum trajectory of substituent permutations of those following from it (in this first section), and set it as the beginning ingress point for the range of those comparable but sufficiently divergent from those in full homogeneity of structure and function to distinguish a more median class that is not in as much a rigid stereotyped placement to both (and not yet approaching the fringe or outermost terms allowing inclusion)

Tematropium, an anticholinergic that diverges from the MAT relational criteria for being a functional analog to cocaine.^[33] (cf. tropatepine)

pFBT: Zatosetron: Tropanserin: Bemesetronum:

• 3-(p-Fluorobenzoyloxy)tropane (30% stimulant potency of cocaine & equipotent as an anaesthetic)
• Zatosetron (anxiolytic & antinauseant 5HT₃ receptor antagonist)
• Tropanserin (migraine medication, potent & selective 5HT₃ antagonist)
• Bemesetronum (antiemetic, mechanisms related to oxytocin function, serotonin D-receptors, cholinoreceptors of the muscarinic or nicotinic kind and histamine H₁-receptors^[34])

cf. Tropisetron

Convolamine: Phyllalbine:
Similarly, many natural tropane alkaloids found in plants of various families have benzoyl tropane structures. Including; catuabine, convolamine of the convolvulaceae & phyllalbine of euphorbiaceae (Phyllanthus discoïdes) families. The latter is a central and peripheral sympathomimetic drug.^[35] Phyllalbine is also to methylvanillylecgonine what tropacocaine, as a metabolite, is to cocaine. Likewise vanillin would be a hydrolytic degradation product of phyllalbine just as methyl benzoate is for cocaine.

Other tropanyl compounds (naturally found or otherwise) begin to fall outside the spectrum of functional analogues to cocaine altogether; having negligible affinity of any kind for the monoamine system. Compare for example ipratropium, mirisetron, technepine, levomepate or scopolamine & atropine. Many of the natural varieties being deliriants.

NK-1145: EGIS-3886: cpd #278^{[lower-alpha 39]} (mono-phenyl benztropine):
The benzoyloxy can even be replaced with other branch formations (terminating in a benzene ring) and the bridge between will still serve to create a parasympatholytic drug compound that causes behavioral stimulation, as the above: NK-1145 "tropine-3β-phenyl ether."^[36] Deramciclane (EGIS-3886) is a camphor derived serotonergic. Similar to several other kinds of aromatics in structure and being an inverse agonist at the 5-HT_2C receptor as well as an antagonist at the 5-HT_2A.

Azaprocin: Pseudotropinearylether:

• Azaprocin (a fast onset, short duration opioid analgesic with tropane emulating every constituent element shared by cocaine; somewhat similar to how fentanyl overlays methylphenidate, save for in that case there's an additional constituent of a phenylethyl tail). Also of note: the arene-fluorinated pseudotropinearylether with respect to U.S. Patent 4,861,889

Piperidine Analogues

3-dimensional (space-filling) rendering of piperidine structure-based, MAT re-uptake inhibiting functional stimulant: "methylphenidate" (MPH)

See: List of methylphenidate analogues

Many of the piperidine analogues of cocaine serve as the 'missing link' between the cocaine structure and that of the methylphenidate class of drugs. For example, DMNPC preserves an orientation similar to the phenyltropanes, but is a structural isomer of methylnaphthidate.

The above depicts the 3D structure of the above-mentioned methylnaphthidate shown with the same modeling for the cocaine derivative WIN 35428, a simple phenyltropane with a short addition to its para position. This overlay shows the closeness of where the two hold their respective oxygen and nitrogens in their structure (also their benzene & cycloalkane ring formations) and is meant to convey a sense of their similarity for binding to MAT. Correspondingly most other monoamine reuptake inhibitors bind to the dopamine transporter substrate recognition site at Tm loci 1, 7 & 10—12; whereas cocaine & methylphenidate similarly share the 1 & 7 places, but diverge from the usual ligand site of the latter and instead cohabit the 9—11 loci.^{[lower-alpha 40]} Site-directed mutagenesis techniques have elucidated that the hydrophobic putative transmembrane regions at one & seven contain aspartate and serine residues, and that the carboxyl-group interacts with the former aspartic acid residue 79 which engages with cocaine & methylphenidate's protonated nitrogen at the transporter.^{[lower-alpha 41]} Previous theories of an allosteric site for cocaine and related compounds which do not overlap with the binding site of dopamine itself are less prevalent in light of more recent observations since LeuT became feasible as a modeling template.^[38]

One rationale to denote the subjective preference for cocaine over methylphenidate in animal habituation & human addiction models has to do with the respective difference in their entropy of binding: cocaine being —5.6 kcal/mol & methylphenidate being —25.5 kcal/mol (Δs°, measured using [³H]GBR 1278 @ 25 °C)^{[lower-alpha 42]}

• JZ-IV-10 (a "Modafinil hybrid" with nocaine.^[39] cf. List of modafinil analogues)

• Nocaine

A somewhat recent occurrence among tentative modern folklore which has traversed the circling of rumors mostly confined to the likes of universities and popular culture trivia has been that cocaine is one element, or molecule increment of weight or charge etc., away from the molecular structure of sugar.^[40] Though such a statement is false as a general pretense, there is a dextrose based super-structure that has a vaguely similar overlay with cocaine which is "benzoyl-beta-D-glucoside."

• Benzoyl-beta-D-glucoside

Benztropine (3α-Diphenylmethoxy Tropane) Analogs

• Benzatropine (BZT)^[41]
• Difluoropine (O-620), More selective as a DARI than cocaine. Also an anticholinergic & antihistamine.
• AHN 1-055 Same structure as for benztropine but 4′,4′-bisfluorinated.
• GA 103 N-phenylpropyl bis-4-fluorobenztropine.
• JHW 007^[42] N-(n-butyl)-3α-[bis(4′-fluorophenyl)methoxy]-tropane.

Unlike cocaine & phenyltropanes, the benztropines & GBR compounds (and, as an exception to the cocaine pharmacophore itself, allotropacocaine) among others are considered "atypical" DAT re-uptake pump ligands because they stabilize the dopamine transporter in an inward-facing or closed-to-out conformation, this contrasts what is considered "cocaine-like" affinity to DAT; which would instead keep DAT stable in an open-to-out conformation. This means the binding of many dopamine reuptake inhibitors is atypical of cocaine's method of binding to DAT and significantly diverges from it.^[43]

"Difluoropine" is not a phenyltropane but actually belongs to the benzatropine family of DRIs. Not to be confused for the "diaryl"-phenyltropanes.

In certain respects these are important because they share SAR overlap with GBR 12909 and related analogs.

SARs have shown that 4′,4′-difluorination is an excellent way to boost DAT activity of benztropine, and gives excellent selectivity over the SERT and the NET.^[44][45]

Furthermore, replacing the N-Me with, e.g. n-phenylpropyl helps to bring muscarinic activity down to something that is the same as DRI affinity.^[44]

This is remarkable considering unmodified (native) benztropine is 60 times more active as an anticholinergic than as a dopaminergic.^[44]

M1 receptor considerations aside, analogues of this benztropine class still won't substitute for cocaine, and have no propensity to elevate locomotor activity.

Compound 276

3α-Diphenylmethoxy tropanes
(Benztropine analog affinities binding to DAT & DA uptake)^{[lower-alpha 43]}

Compound	S. Singh's alphanumeric assignation (name)	R	R′	Ki (nM) [3H]WIN 35428 binding	IC50 (nM) [3H]DA uptake	Selectivity uptake/binding
	(Cocaine)			388 ± 47	-	-
	(GBR 12909)			11.6 ± 31	-	-
	(Benztropine)	H	H	118 ± 9	403 ± 115	3.4
	249a	4′-F	H	32.2 ± 10	48	1.5
	249b (AHN 1-055)	4′-F	4′-F	11.8 ± 1	71	6.0
	249c	3′,4′-di-F	H	27.9 ± 11	181 ± 45.7	6.5
	249d	4′-Cl	H	30.0 ± 12	115	3.8
	249e	4′-Cl	4′-Cl	20.0 ± 14	75	3.8
	249f	3′,4′-di-Cl	H	21.1 ± 19	47	2.2
	249g	3′,4′-di-Cl	F	18.9 ± 14	24	1.3
	249h	4′-Br	H	37.9 ± 7	29	0.8
	249i	4′-Br	4′-Br	91.6	34	0.4
	249j	4′-NO2	H	197 ± 8	219	1.1
	249k	4′-CN	H	196 ± 9	222	1.1
	249l	4′-CF3	H	635 ± 10	2155	3.4
	249m	4′-OH	H	297 ± 13	677	2.3
	249n	4′-OMe	H	78.4 ± 8	468	6.0
	249o	4′-OMe	4′-OMe	2000 ± 7	2876	1.4
	249p	4′-Me	H	187 ± 5	512	2.7
	249q	4′-Me	4′-Me	420 ± 7	2536	6.0
	249r	4′-Et	H	520 ± 8	984	1.9
	249s	4′-t-Bu	H	1918	4456	2.3
	250a	3′-F	H	68.5 ± 12	250 ± 64.7	3.6
	250b	3′-F	3′-F	47.4 ± 1	407 ± 63.9	8.6
	250c	3′-Cl	H	21.6 ± 7	228 ± 77.1	10.5
	250d	3′-CF3	H	187 ± 5	457 ± 72.0	2.4
	251a	2′-F	H	50.0 ± 12	140 ± 17.2	2.8
	251b	2′-Cl	H	228 ± 9	997 ± 109	4.4
	251c	2′-Me	H	309 ± 6	1200 ± 1.64	3.9
	251d	2′-NH2	H	840 ± 8	373 ± 117	0.4

3α-Diphenylmethoxy-2β-carbomethoxybenztropine
(Benztropine affinities to DAT & 5-HTT in cynomologous monkey caudate-putamen)^{[lower-alpha 44]}

Compound	S. Singh's alphanumeric assignation (name)	R	R′	IC50 (nM) DAT (Binding of [3H]WIN 35428)	IC50 (nM) 5-HTT (Binding of [3H]Citalopram)	Selectivity 5-HTT/DAT
	(benztropine)			312 ± 1.1	24100 ± 14800	77.2
	(WIN 35428)			12.9 ± 1.1	160 ± 20	12.4
	R-256			2040 ± 283	1460 ± 255	0.7
	S-257a	H	H	33.5 ± 4.5	10100 ± 1740	301
	S-257b	H	F	13.2 ± 1.9	4930 ± 1200	373
	S-257c (difluoropine)	F	F	10.9 ± 1.2	3530 ± 1480	324
	S-257d	H	Cl	15.8 ± 0.95	5960 ± 467	377
	S-257e	Cl	Cl	91.4 ± 0.85	3360 ± 1480	36.8
	S-257f	H	Br	24.0 ± 4.6	5770 ± 493	240
	S-257g	Br	Br	72.0 ± 3.65	2430 ± 339	33.7
	S-257h	H	I	55.9 ± 10.3	9280 ± 1640	166
	S-257i	Br	I	389 ± 29.4	4930 ± 82	12.7
	S-257j	I	I	909 ± 79	8550 ± 442	9.4
	S-257k	H	Me	49.5 ± 6.0	13200	266
	S-257l	Me	Me	240 ± 18.4	9800 ± 2680	40.8

Compound 277

N-Modified 2-carbomethoxybenztropines
(Benztropine affinities to DAT & 5-HTT in cynomologous monkey caudate-putamen)^{[lower-alpha 45]}

Compound	S. Singh's alphanumeric assignation (name)	R	n	IC50 (nM) DAT (Binding of [3H]WIN 35428)	IC50 (nM) 5-HTT (Binding of [3H]Citalopram)	Selectivity 5-HTT/DAT
	258a			20.3 ± 3.5	-	-
	258b	H	1	223 ± 53	4970 ± 700	22.3
	258c	H	3	22.0 ± 11.9	19.7 ± 3	0.9
	258d	Br	3	80.2 ± 8.8	234 ± 0.5	2.9
	258e	I	3	119 ± 11	2200 ± 1250	18.5
	258f	H	5	99.0 ± 28	550 ± 63	5.5
	259			616 ± 88	55200 ± 20000	89.3

N-substituted 3α[bis(4′-fluorophenyl)methoxy]tropanes
(Benztropine affinities to DAT & 5-HTT)^{[lower-alpha 46]}

Compound	S. Singh's alphanumeric assignation (name)	R	Ki (nM) DAT (Binding of [3H]WIN 35428)	IC50 (nM) 5-HTT (Uptake of [3H]DA)	Selectivity uptake/binding
	260 (AHN 2-003)	H	11.2 ± 11	9.7	0.9
	261a	3-phenylpropyl	41.9 ± 11	230	5.5
	261b	indole-3-ethyl	44.6 ± 11	1200	26.9
	261c	4-phenylbutyl	8.51 ± 14	39	4.6
	261d	4-(4′-nitrophenyl)butyl	20.2 ± 11	650	32.2
	261e	3-(4′-fluorophenyl)propyl	60.7 ± 12	-	-
	262a	n-butyl	24.6 ± 8	370	15.0
	262b	cyclopropylmethyl	32.4 ± 9	180	5.5
	262c	allyl	29.9 ± 10	14	0.5
	262d	benzyl	82.2 ± 15	290	3.5
	262e	4-fluorobenzyl	95.6 ± 10	200	2.1
	262f	cinnanyl	86.4 ± 12	180	2.1
	262g	[bis(4-fluorophenyl)methoxy]ethyl	634 ± 23	-	-
	262h	[(4-nitrophenyl)phenylmethoxy]ethyl	57.0 ± 17	-	-
	263	acetyl	2340	4600	2.0
	264	formyl	2020 ± 13	5400	2.7
	265a	Ts	0%ɑ	-	-
	265b	Ms	18%ɑ	-	-
	(AHN 2-005)[46]	CH2CH=CH2	-	-	-
	(JHW 007)[46]	CH2CH2CH2CH3	-	-	-
	(GA 2-99)[46]	CH2CH2NH2	-	-	-
	(GA 103)[46]	CH2CH2CH2CH2Ph	-	-	-
	266		108 ± 12	130	1.2

^ɑInhibition at 10 µM

Deuterium labeled radio-ligand of benztropine analog JHW-007; a di-para-fluoro benztropine, and hybrid between benzatropine & difluoropine (with fluorine groups in the former to breach the difference or the latter being descarbmethoxy to approach identification with the former).

8-Oxa-2-carbomethoxy norbenztropines
(8-Oxanortropane benztropine analog affinities to DAT & 5-HTT)^{[lower-alpha 47]}

Compound	S. Singh's alphanumeric assignation (name)		IC50 (nM) DAT (Binding of [3H]WIN 35428)	IC50 (nM) 5-HTT (Binding of [3H]Citalopram)
	R/S-268	2β,3β	>10000	>1660
	R/S-269	2α,3β	20300	>1660
	R/S-270	2α,3α	22300	>1660
	R/S-271	2β,3α	520	>1660

8-Aminopentacyclo (σ receptor ligand) Trishomocubane Analogs

cf. other trishomocubanes such as basketane.

Polycyclic cage molecules: N-substituted 8-aminopentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecanes (AHDs) & related.
The 3-FPh, 14b, has 1.2 ± 0.1 K_i (nM ± SEM) @ DAT.^[47]

Bicyclic Amine Analogues

• EXP-561

Quinuclidine Analogues

• Butyltolylquinuclidine

Miscellaneous loosely analogous stimulants

Chromen-2-one (SNDRI compound) US 2011136854  IUPAC name DA-uptake IC50(μM) NA-uptake IC50(μM) 5-HT-uptake IC50(μM) 7-(((1R,3r,5S)-9-Azabicyclo[3.3.1]nonan-3-yl)oxy)-2H-chromen-2-one 0.0013 0.24 0.076 7-(((1R,3r,5S)-9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)oxy)-2H-chromen-2-one 0.0029 0.15 0.27

Benzoates (Structures with both stimulant & local anesthetic effects)

• Dimethocaine/Larocaine (DMC) (An aniline)
• Nitracaine

See some of Robert Clarke's contributions

Organochlorides

Org 6582
A potent and long-lasting monoamine re-uptake inhibitor used in drug research.

• Diclofensine
• LR-5182

Quinolizidines

• Quinolizidine analogues of piperidine methylphenidate structure

2,3-Benzodiazepines

Spirocyclic tropanyl-Δ(2)-isoxazoline compound:

3′-methoxy-8-methyl-spiro(8-azabicyclo(3.2.1)octane-3,5′(4′H)-isoxazole which allosterically enhances SERT binding of other reuptake ligands. Construed as a potentiating allosteric effect (by unveiling occluded configured serotonin uptake-area ligand-site on surface of transporter that allows for binding by exogenous ligand, when SERT is otherwise conformed in a transitional manner where a SERT ligand cannot bind, this effect with compound in question occurs) at concentrations of 10μM—30μM (wherein it acts by interconverting the conformational state of unexposed SERTs to ones exposing the SSRI binding site via a shift to the equilibrium of the MAT) while exerting an inhibitory orthosteric effect when concentrations reach >30μM and above. This is the only known compound to allosterically modulate SERT in such a way within in vitro conditions (tianeptine has been shown to do similar, but has only shown efficacy doing so in living in vivo tissue samples). Considering its noncompetitive inhibition of 5-HT transporters decreasing V_max with small change in the Km for serotonin, putatively stabilizing the cytoplasm-facing conformation of SERT: in such respect it is considered to have the opposite effect profile of the anti-addiction drug ibogaine (save for the function by which its anti-addictive properties are thought to be mediated, i.e. α₃β₄ nicotinic channel blockage. cf. 18-Methoxycornaridine for such nicotinergic activity without the likewise SERT affinity).^[48]

• GYKI-52895

Phenethylamines

Methylenedioxypyrovalerone: Prolintane: α-Pyrrolidinopropiophenone:

Many phenethylamines are dopamine releasers, however, certain drugs of the family inhibit dopamine reuptake & transport which may be loosely classed as cocaine analogs. Dependent upon their specific configurations. Like has been shown with cocaine, methylenedioxypyrovalerone (MDPV) has been shown to similarly be neuroprotective against the neural damage caused by amphetamine type drugs (i.e. releasers)^[49]

Adamantanes

• A-77636

• Bromantane

Pyridines

• Altinicline

Nicotinic agonist which stimulates the release of dopamine.

Naphthyridines

Desmethoxyyangonin (5,6-dehydrokawain), reversible MAO-B inhibitor believed to contribute to mediating dopamine release in nucleus accumbens.

• Amfonelic acid

Being a carboxylic acid, amfonelic acid could potentially be used as a carboxylate for the protonation to the free base of another compound; even conceivably creating a 'cocaine amfonelate' or 'cocaine AFA' as opposed to cocaine HCl, cocaine citrate or cocaine HBr et cetera wherein such a case it's conjugate used to form it as a salt would additionally be dopaminergic.

Quinazolinamines (Allosteric functional DAT reuptake inhibitors)

• SoRI-20041
• SoRI-9804

cf. the benztropine phenyltropanes:

SoRI-20041 is a functional, but not structural, cocaine analog which violates traditional structure analog categorization in its case that it has an entirely other binding site. It is however an analog to cocaine in the sense that it functions as a partial DARI on DAT, although doing so when said DAT is compromised by amphetamine-type mediated release of DA. Something unaugmented cocaine cannot do. It nevertheless performs the role of an analogous adjunct to cocaine's function for phosphorylated DAT. It is however worth noting that as for its structure, it displays a certain degree of shared conformation with the benztropine phenyltropanes.

Piperazines (Aryl-1,4-dialkyl piperazines)

Methylphenidate rendered in 3D (in blue) overlaid with 1-(2-Phenylethyl) piperazine skeleton (turquoise) showing the basic 3- point pharmacophore shared between them and other dopamine reuptake inhibitors such as 3C-PEP (that itself is only a 3-chlorophenyl more than 1-(2-Phenylethyl) piperazine).

GBR-13098: 281 (decanoate 5):

• GBR-13098
• DBL-583

GBR compounds were derived from the benztropines by replacing their tropane nucleus with a piperazine ring (and therefore constitute being congeners with cocaine).^{[lower-alpha 48]} The name "GBR" is derived from its maker Gist-Brocades (now DSM), Netherlands.

cf. to the GBRs the non-diphenyl and still quite highly specific dopaminergic (selective) stimulant 3C-PEP; shown to be roughly 10,000× more potent than cocaine as a DAT reuptake inhibitor. There are other related stimulants structurally.^[50]

GBR compounds are sometimes broadly classed as being, and referred to by the term, "rimcazole analogs"^[51] - for example the compounds: JJC 1-059, JJC 2-010, and JJC 2-006.^[46]

GBR 12783 analogues inhibition of DAT binding & DA uptake^{[lower-alpha 49]}

Compound	S. Singh's alphanumeric assignation (name)	R	Ki (nM) [3H]WIN 35425	IC50 (nM) [3H]DA	Selectivity DA/DAT uptake/binding
	(Cocaine)		224 ± 3.4	208 ± 7.4	0.93
	(WIN 35428)		24 ± 3.1	14 ± 1.8	0.58
	(DA)		10000 ± 2400	44 ± 5.3	0.004
	279 (GBR 12909/Vanoxerine)		27 ± 4.1 0.06 ± 0.02b 52.8 ± 4.4c >20,000d	0.21 ± 0.06	0.007 880e >333,333.3f
	282 (GBR 12783)	H	12 ± 1.2ɑ	-	-
	284a	3-NH2	12 ± 1.0	7 ± 3.5	0.58
	284b	3-NCS	160 ± 17	106 ± 37	0.67
	284c	4-NH2	11 ± 0.7	1.6 ± 0.2	0.14
	284d	4-NO2	26 ± 9.3	2.7 ± 0.1	0.10
	284e	4-NCS	159 ± 12	26 ± 1.8	0.16
	284f	4-maleimide	2327 ± 1000	476 ± 61	0.20

• ^ɑIC₅₀ for inhibiting [³H]methylphenidate
• ^bK_i (nM) for inhibiting [³H]GBR 12935
• ^cK_i (nM) for inhibiting [³H]Paroxetine @ 5-HTT
• ^dK_i (nM) for inhibiting [³H]Nisoxetine @ NET
• ^eSelectivity between 5-HTT/DAT
• ^fSelectivity between NET/DAT

GBR analogue compounds with piperazine ring-alterations. Binding affinities and inhibition of uptake for DA & 5-HT.^{[lower-alpha 50]}

Compound	S. Singh's alphanumeric assignation (name)	R	X-Y (289-290) R1 (298)	IC50 (nM) [3H]GBR 12935 binding	IC50 (nM) [3H]DA uptake	IC50 (nM) [3H]5-HT uptake	Selectivity [3H]DA uptake/DAT binding	Selectivity [3H]5-HT/[3H]DA uptake
	(Cocaine)			660 ± 30 (Ki value)	478 ± 25	304 ± 10	0.72	0.64
	(GBR 12935)			4.1 ± 0.6	3.7 ± 0.4	289 ± 29	0.90	78.1
	279 (GBR 12909)			5.5 ± 0.4	4.3 ± 0.3	73 ± 1.5	0.78	17.0
	289a	H	C-C	21 ± 1.0	9.6 ± 1.5	1720 ± 70	0.46	179
	289b	F	C-C	40 ± 1	15 ± 2	459 ± 26	0.37	30.6
	(-)289b (2S,5R)	F	C-C	3.6 ± 0.14	8.1 ± 0.3	-	2.25	-
	(+)289b (2R,5S)	F	C-C	125 ± 7.0	87 ± 4.1	-	0.70	-
	289c	H	C=C	103 ± 13	20 ± 4	2680 ± 122	0.19	134
	289d	F	C=C	23 ± 3	28 ± 5	1180 ± 404	1.22	42.1
	290a (LR1111)	H	C-C	7.9 ± 1.7	7.2 ± 0.5	34100 ± 359	0.91	4736
	290b	F	C-C	4.4 ± 0.4	3.4 ± 0.4	112 ± 24	0.77	32.9
	290c	H	C=C	8.6 ± 1.1	0.6 ± 0.1	503 ± 103	0.07	838
	290d	F	C=C	2.6 ± 0.4	3.4 ± 0.4	234 ± 10	1.31	68.8
	291			286 ± 8	87 ± 5	3150 ± 491	0.30	36.2
	292			864 ± 91	93 ± 6	1590 ± 60	0.11	17.1
	293			27 ± 4	18 ± 1	2450 ± 57	0.67	136
	294			169 ± 5	83 ± 7	1890 ± 268	0.49	22.8
	295			80 ± 6	35 ± 2	376 ± 19	0.44	10.7
	296			74 ± 5	57 ± 10	2860 ± 45	0.77	50.2
	297			20 ± 0.7	9.3 ± 1.8	1480 ± 69	0.46	159
	(-)298a	H	H	5.1 ± 0.4	0.7 ± 0.05	986 ± 34	0.14	1409
	(+)298a	H	H	747 ± 163	127 ± 10	3210 ± 450	0.17	25.3
	(-)298b	F	H	104 ± 8	29 ± 2	20100 ± 2400	0.28	693
	(-)298c	H	OH	222 ± 13	31 ± 0.1	857 ± 17	0.14	27.6

Heteroaromatic and fused ring GBR analogue affinities reuptake inhibition for DA & 5-HT and [¹²⁵I]RTI-55 labeled DAT & 5-HTT binding affinities.^{[lower-alpha 51]}

Compound	S. Singh's alphanumeric assignation (name)	R	R1	IC50 (nM) [125I]RTI-55 binding DAT	IC50 (nM) [125I]RTI-55 binding 5-HTT	IC50 (nM) reuptake [3H]DA	IC50 (nM) reuptake [3H]5-HT	Selectivity binding 5-HTT/DAT	Selectivity uptake [3H]5-HT/[3H]DA
	(GBR 12935)	C6H5		3.7 ± 0.3	623 ± 13	3.7 ± 0.4	298 ± 29	168	80.5
	304a	2-thienyl		5.2 ± 0.3	842 ± 30	9.7 ± 0.2	1990 ± 58	162	205
	304b	2-furyl		6.5 ± 0.2	1520 ± 47	8.5 ± 0.5	2550 ± 87	34	300
	304c	2-pyridyl		78 ± 4	2420 ± 65	70 ± 6	3700 ± 148	31.0	52.8
	279 (GBR 12909)	C6H5		3.7 ± 0.4	126 ± 5	7.3 ± 0.2	73 ± 2	34.0	10.0
	305a	2-thienyl		3.3 ± 0.1	105 ± 2	6.1 ± 0.7	335 ± 17	31.8	54.9
	305b	2-furyl		5.9 ± 0.3	204 ± 7	7.9 ± 0.5	412 ± 9	34.6	52.1
	305c	2-pyridyl		16 ± 0.2	2800 ± 139	20 ± 0.8	6520 ± 293	175	326
	282 (GBR 12783)	C6H5		-	-	-	-	-	-
	306a	2-thienyl		6.4 ± 0.3	1170 ± 31	10 ± 0.7	2020 ± 141	183	202
	306b	2-furyl		5.0 ± 0.3	1840 ± 59	9.6 ± 0.3	2700 ± 136	368	281
	306c	2-pyridyl		44 ± 3	2670 ± 66	64 ± 2	3620 ± 179	60.7	56.6
	283 (GBR 13069)	C6H5		0.9 ± 0.1	135 ± 7	11 ± 0.6	576 ± 32	150	52.4
	307a	2-thienyl		2.2 ± 0.1	88 ± 2	13 ± 1.4	374 ± 17	40.0	28.8
	307b	2-furyl		1.8 ± 0.3	109 ± 4	7.2 ± 0.4	442 ± 23	60.5	61.4
	307c	2-pyridyl		13.6 ± 0.2	334 ± 12	14.5 ± 1.9	666 ± 21	24.5	45.9
	308a	H	(benzothiophen-2-yl)methyl	18.1 ± 1	2420 ± 109	19 ± 1	3520 ± 289	134	185
	308b	F	(benzothiophen-2-yl)methyl	4.1 ± 1.1	495 ± 18	34 ± 2	1230 ± 40	121	36.2
	309a	H	(benzofuran-2-yl)methyl	17 ± 0.5	1890 ± 48	22 ± 0.7	3040 ± 213	111	138
	309b	F	(benzofuran-2-yl)methyl	6.4 ± 0.2	286 ± 10	18.6 ± 0.6	767 ± 27	44.7	41.2
	310a	H	(indol-2-yl)methyl	1.1 ± 0.1	668 ± 39	8.8 ± 0.7	2120 ± 166	607	241
	310b	F	(indol-2-yl)methyl	0.7 ± 0.1	119 ± 5	13 ± 0.2	506 ± 23	170	38.9
	311a	H	(benzimidazol-2-yl)methyl	46 ± 1	1884 ± 72	37 ± 2	4076 ± 221	41.0	110
	311b	F	(benzimidazol-2-yl)methyl	15 ± 0.2	256 ± 7	20 ± 0.8	797 ± 43	17.1	39.8
	312a	H	(quinolin-2-yl)methyl	199 ± 5	1990 ± 5	192 ± 8	4120 ± 212	10.0	21.5
	312b	F	(quinolin-2-yl)methyl	56 ± 1	51 ± 16	106 ± 12	339 ± 31	0.9	3.2
	313a	H	(quinolin-3-yl)methyl	72 ± 2	1160 ± 27	111 ± 3	3040 ± 252	16.1	27.4
	313b	F	(quinolin-3-yl)methyl	16 ± 3	485 ± 16	74 ± 3	851 ± 36	30.3	11.5
	314a	H	(quinolin-6-yl)methyl	190 ± 6	845 ± 15	140 ± 4	1640 ± 58	4.4	11.7
	314b	F	(quinolin-6-yl)methyl	62 ± 2	551 ± 21	73 ± 3	1040 ± 46	8.9	14.2
	315a	H	3-(benzimidazol-2-yl)propyl	23 ± 0.5	309 ± 9	17 ± 0.7	627 ± 12	13.4	36.9
	315b	F	3-(benzimidazol-2-yl)propyl	2.5 ± 0.1	28 ± 2	8.1 ± 0.3	74 ± 4	11.2	9.1
	316a	H	(naphthalen-2-yl)methyl	43 ± 2	903 ± 47	32 ± 0.6	926 ± 33	21.0	28.9
	316b	F	(naphthalen-2-yl)methyl	8.0 ± 0.3	312 ± 15	30 ± 1	588 ± 39	39.0	19.6
	317a	H	(naphthalen-1-yl)methyl	114 ± 5	336 ± 22	406 ± 11	83 ± 5	2.9	0.2
	317b	F	(naphthalen-1-yl)methyl	31 ± 1	243 ± 6	312 ± 19	257 ± 12	7.8	0.8
	318a	H	2-(naphthalen-1-yl)ethyl	92 ± 13	462 ± 17	42 ± 0.9	578 ± 17	5.0	13.8
	318b	F	2-(naphthalen-1-yl)ethyl	7.8 ± 0.2	46 ± 1	25 ± 0.8	119 ± 4	5.9	4.8

Piperidine analogues of piperazine GBR compounds & their affinity to bind at DAT & 5-HTT^{[lower-alpha 52]}

Compound	S. Singh's alphanumeric assignation (name)	R	R′	R″	IC50 (nM) DAT [3H]WIN 35428	IC50 (nM) 5-HTT [3H]citalopram	Selectivity 5-HTT/DAT
	279 (GBR 12909)				14.0 ± 0.6	82 ± 4	5.8
	320 (O-549)				595 ± 148	38 ± 127	0.6
	321 (O-526)	F			24.9 ± 3.23	248 ± 72	9.9
	322a	H			12.0 ± 0.4	232 ± 28	19.3
	322b	Cl			65.0 ± 12	224 ± 10	3.4
	322c	Br			159 ± 56	835 ± 142	5.2
	322d	OCH3			255 ± 32	340 ± 24	1.3
	323a	H			10.6 ± 0.85	102 ± 5	9.6
	323b	F			19.9 ± 9.5	31.9 ± 7.1	1.6
	323c	Cl			115 ± 22	414 ± 32	3.6
	323d	Br			382 ± 167	638 ± 71	1.7
	323e	CH3			311 ± 71	888 ± 58	2.8
	324a	H			15.2 ± 2.8	743 ± 6	48.9
	324b	F			9.7 ± 0.4	198 ± 7	20.4
	325a	H			14.5 ± 1.9	58 ± 7	3.7
	325b	F			13.0 ± 2.5	112 ± 4	8.6
	326a	H			108 ± 14	456 ± 90	4.2
	326b	F			13.5 ± 2.6	237 ± 53	17.5
	327a	H			702 ± 34	544 ± 91	0.8
	327b	F			126 ± 13	761 ± 101	6.0
	328a	H	H	F	17.2 ± 4.7	1920 ± 233	111.6
	328b	H	H	Cl	24.7 ± 5.5	1610 ± 119	65.2
	328c	H	H	Br	31.1 ± 2.9	1490 ± 319	47.9
	328d	H	Cl	Cl	85.7 ± 4.7	2880 ± 281	33.6
	328e	H	H	OCH3	27.8 ± 6.8	1240 ± 342	44.6
	328f	Cl	H	F	52.4 ± 7.8	1810 ± 107	34.5
	328g	F	H	F	14.0 ± 3.3	1260 ± 72	90.0
	328h	H	H	CH3	23.0 ± 3.7	1390 ± 240	60.4
	328i	H	Cl	F	28.2 ± 3.1	2530 ± 50	89.7
	328j	H	H	NO2	16.4 ± 3.0	1770 ± 305	107.9
	328k	H	H	NH2	101 ± 13	1570 ± 201	15.5
	329a	Ph	3-pyridyl		48.6 ± 8.4	680 ± 12.0	14.0
	329b	Ph	2-benzo[b]thiophenyl		172 ± 16.4	1540 ± 251	8.9
	329c	Ph	2-thienyl		59.3 ± 5.8	1250 ± 87	21.1
	329d	2-thienyl	Ph		27.2 ± 0.1	741 ± 108	27.2
	329e	2-thienyl	4-F-Ph		13.8 ± 3.4	1390 ± 243	101
	329f	2-thienyl	3-pyridyl		58.3 ± 5.7	927 ± 34	15.9
	330a	F	4-F-Ph		15.1 ± 2.0	75.8 ± 22.1	5.0
	330b	F	Ph		41.4 ± 8.0	271 ± 18.4	6.5
	330c	H	Ph		10.1 ± 1.6	231 ± 4.5	22.9
	330d	H	4-F-Ph		10.8 ± 3.2	205 ± 13.3	19.0
	330e	H	2-thienyl		9.8 ± 2.4	290 ± 63	29.6
	331a	Ph	H	4-F-Ph	6.6 ± 1.4	223 ± 32.3	33.8
	331b	Ph	H	3-pyridyl	29.9 ± 0.3	194 ± 20.1	6.5
	331c	2-thienyl	H	Ph	6.0 ± 0.5	180 ± 21.6	30.0
	331d	2-thienyl	F	Ph	11.7 ± 1.0	85.7 ± 2.6	7.3
	332a	H	F		9.4 ± 2.6	585 ± 101	62.2
	332b	F	H		-	-	-

Dihydroimidazoles

Possible substitutions of the Mazindol molecular structure.

See: List of Mazindol analogues

Mazindol is usually considered a non-habituating (in humans, and some other mammals, but is habituating for e.g. Beagles^{[lower-alpha 53]}) tetracyclic dopamine reuptake inhibitor (of somewhat spurious classification in the former).

It is a loosely functional analog used in cocaine research; due in large part to N-Ethylmaleimide being able to inhibit approximately 95% of the specific binding of [³H]Mazindol to the residues of the MAT binding site(s), however said effect of 10 mM N-Ethylmaleimide was prevented in its entirety by just 10 μM cocaine. Whereas neither 300 μM dopamine or D-amphetamine afforded sufficient protection to contrast the efficacy of cocaine.^{[lower-alpha 54]}

The above steps in its synthesis show the similitude of its precursors to the MAT reuptake inhibitor pipradrol & related compounds.

Local anesthetics (not usually CNS stimulants)

Amylocaine, or Stovaine (above), the first synthetically constructed local anesthetic. Compare structure to dimethylaminopivalophenone (below), an analgesic (opioid). Interestingly, cocaine's classification as a narcotic under U.S. legal code, as has been stretched to be medicinally rationalized such when defining terms very broadly (due to its topical numbing affect, hindering pain signals from CNS recognition via local anesthesia) usually considered an exaggeration of traditional medicine naming convention, in this instance between the first synthetic sodium channel blocker and one of the very simplest opioids there remains a measure of apparent structural similarity between the former anesthetic and latter analgesic "narcotics"; despite the highly differing methods of action for the respective 'pain-killing' properties of either.^[52]

β-Eucaine (Betacain)

In animal studies, certain of the local anesthetics have displayed residual dopamine reuptake inhibitor properties,^[53] although not normally ones that are easily available. These are expected to be more cardiotoxic than phenyltropanes. For example, dimethocaine has behavioral stimulant effects (and therefore not here listed below) if a dose of it is taken that is 10 times the amount of cocaine. Dimethocaine is equipotent to cocaine in terms of its anesthetic equivalency.^[53] Intralipid "rescue" has been shown to reverse the cardiotoxic effects of sodium channel blockers and presumably those effects when from cocaine administered intravenously as well.

Analogues for other purposes

Tropanes (Non-ecgonine)

• Homatropine
• Methylhomatropine

Benzamides

Mefexamide is not a benzamide, but it has structure that is related and is described as a central stimulant, and therefore more correctly a "functional analog". cf. the benzoate stimulants

• Procainamide (also an aniline, like dimethocaine)

Toxins

Cocaine to Anatoxin-a:^[55]

• Anatoxin-a, also known as "Very Fast Death Factor" (VFDF), is an acutely toxic cyanotoxin with a method of action as an agonist of acetylcholine via those nicotinic class of receptors. Cocaine can be used as a precursor in its synthesis.

VFDF Note its eight, instead of seven, sides (not counting the nitrogen-bridge inside ring)

cf. methylecgonidine, a pyrolysis product of cocaine freebase.

cf. also: ferruginine, a compound even more analogous to the former.[56]

UB-165, a nAChR agonist of a subtype with a function leading to release of dopamine and noradrenaline in the brain.

• Epibatidine (cf. nicotine)
• Pinnamine

• 3-Quinuclidinyl benzilate^[57] (synthetic deliriant used as incapacitating agent)

See also

Cocaine-N-oxide: Hydroxytropacocaine: m-Hydroxybenzoylecgonine:

Methylecgonine cinnamate, an alkaloid widely considered inactive in its own right, but postulated to be active under pyrolysis. (cf. alkylphenyltropane analogue "224e") It is, however, found in patents of active cocaine analogue structures.^[58][59]

Cocaine HCl hydrolyzes in moist air and enucleates from on its tropane-skeleton arrangement to become the above compound; methyl benzoate

• Coca alkaloids, the ones relating to cocaine biosynthesis include: benzoylecgonine, ecgonidine, ecgonine, hydroxytropacocaine, methylecgonine cinnamate, tropacocaine & truxilline
• Cocaine metabolites (Human), which include: benzoylecgonine (BE), ecgonine methyl ester (EME), ecgonine, norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE) & m-hydroxybenzoylecgonine
• Dopaminergics
• Federal Analog Act
• Pharmacophore
• Pharmacopoeia
• Pharmacokinetics

Common analogues to prototypical D-RAs:

• Substituted amphetamines
• Substituted cathinones
• Substituted phenethylamines
• Substituted phenylmorpholines
• Substituted methylenedioxyphenethylamines

Notes (inclu. specific locations of citations from within references used)

References

External links

Wikimedia Commons has media related to Cocaine analogs.

• U. S. Provisional Patent Application listing examples of compounds which are tropanes for prospective use in research
• Article on cocaine analogue research
• List of tropanyl type molecules and their CAS Registry Numbers