List of cocaine analogues

This is a list of cocaine analogues. A cocaine analogue is an artificial construct of a novel chemical compound from 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 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:

stereoisomers of cocaine
3β-phenyl ring substituted analogues
2β-substituted analoguesN-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

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 anaesthetics and stimulant dopamine reuptake inhibitor ligands. 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.

Analogs ''sensu stricto''">Structural analog#Chemistry">Analogs ''sensu stricto''

Cocaine Stereoisomers

Structure	Stereoisomer		IC₅₀ tritium\|WIN 3542 inhibition to rat striatal membranes Mean error standard ≤5% in all cases	IUPAC nomenclature
	R-cocaine		102	methyl-3--8-methyl-8-azabicyclooctane-2-carboxylate
	R-pseudococaine	172	15800	methyl-3--8-methyl-8-azabicyclooctane-2-carboxylate
	R-allococaine	173	6160	methyl-3--8-methyl-8-azabicyclooctane-2-carboxylate
	R-allopseudococaine	174	28500	methyl-3--8-methyl-8-azabicyclooctane-2-carboxylate
	S-cocaine	175	15800	methyl-3-oxy-8-methyl-8-azabicyclooctane-4-carboxylate
	S-pseudococaine	176	22500	methyl-3-oxy-8-methyl-8-azabicyclooctane-4-carboxylate
	S-allococaine	177	9820	methyl-3-oxy-8-methyl-8-azabicyclooctane-4-carboxylate
	S-allopseudococaine	178	67700	methyl-3-oxy-8-methyl-8-azabicyclooctane-4-carboxylate

There are eight stereoisomers of cocaine. Due to the presence of four asymmetric carbon atoms in the 1- & 5- to 8 position bond bridge that could adopt R- & S- configurations, cocaine can be considered to have as many as sixteen stereoisomers. However, geometric constraints imparted by the bridgehead amine allow only eight to be created.
The natural isomerism of cocaine is unstable and prone to epimerization. For example, the end product of cocaine biosynthesis contains an axial C2-carbomethoxy moiety which readily undergoes epimerization to the equatorial position via saponification.
For any 2D structural diagrams where stereochemistry is not indicated, it should be assumed the analogue depicted shares the stereochemical conformation of R-cocaine unless noted otherwise.

Arene benzene-ring">Aromatic hydrocarbon">Arene benzene-ring 2′, 3′, 4′ (5′ & 6′) position ([aryl]) substitutions

''para''-substituted benzoylmethylecgonines

183a	183b	183c

183d	4'-Fluorococaine	P-ISOCOC

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.

''meta''-substituted benzoylmethylecgonines

^ɑIC₅₀ value for displacement of cocaine

184a	184b	m-ISOCOC	C3-Benzyloxycocaine

''ortho''-substituted benzoylmethylecgonines

^ɑIC₅₀ value for displacement of cocaine

185a	185b	185c	185d

The hydroxylated 2′-OH analogue exhibited a tenfold increase in potency over cocaine.

Manifold and termination benzoyloxy phenyl-substitutions

Vanillylmethylecgonine	186b

Multi-substitutions or manifold substituted analogues are analogues where more than one modification from the parent molecule takes place. 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.

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

Structure	S. Singh's alphanumeric assignation	C=R	DAT Cocaine
	187	1-naphthalene	742 ± 48
	188	2-naphthalene	327 ± 63

Benzoyl and carbomethoxy branch modifications

Benzoylthiomethylecgonine

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

Cocaine reverse ester (REC)

REC is a cocaine analogue which contains a "reversed" C2 carbomethoxy moiety. In animal studies, REC lacked cocaine-like stimulant effects.

C1-tropane-ring hydrogen—substitutions

Structure	Trivial name		K_i @ DAT	K_i @ SERT	K_i @ NET	σ₁ affinity K_i	σ₂ affinity K_i	IC₅₀ Na+ inhibition ^c
	-Cocaine	H	326 ± 106	513 ± 143	358 ± 69	6.7 ± 0.3 μM^d	"significant"	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 ± 17.0^ɑ	1,106 ± 112	598 ± 179	—	—	—	3.20
	-1-n-propyl-cocaine	n-Pr	871 ± 205^ɑ	2,949 ± 462^b	796 ± 195	—	—	—	3.56
	-1-n-pentyl-cocaine	n-C₅H₁₁	1,272 ± 199^b	1,866 ± 400^ɑ	1,596 ± 21^b	—	—	—	4.64
	-1-phenyl-cocaine	Ph	32.3 ± 5.7^b	974 ± 308	1,980 ± 99^b	524 nM	198 nM	0.29 ± 0.07	3.77

^ɑ, P < 0.05 compared with -cocaine
^b, P < 0.01 compared with -cocaine
^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.
Using same data-set as above table, the following compounds were found to compare as:
*CFT @ DAT = 39.2 ± 7.1
*fluoxetine @ SERT = 27.3 ± 9.2
*desipramine @ NET = 2.74 ± 0.59

Cocaine analogs substituting the C1-tropane ring position, requiring sulfinimine chemistry which bind unlike the typical configuration at DAT as cocaine, or in the atypical conformation of the benztropines. 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.
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, whereas the C1 methyl analog is 2.3 times less potent as a local anesthetic.
cf. hydroxytropacocaine for a natural alkaloid that is a C1 substituent with a hydroxy group.

2''β''-substitutions

Structure	S. Singh's alphanumeric assignation	R	DAT WIN 35428	5-HTT Paroxetine	NET Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	-	-	-	-	-	-	-
		Me	89 ± 4.8	1045 ± 89	3298 ± 293	11.7	37.0
	196a	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	β-phenethyl	61 ± 6	-	-	-	-
	196o	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	-NMe	60 ± 6.4	28162 ± 2565	3935 ± 266	469	65.6
	197d	-NHMe	2424 ± 118	44798 ± 2105	4213 ± 206	18.5	1.7
	197e	-OH	195000	-	-	-	-
	197f	HOCH₂-	561 ± 149	-	-	-	-
	197g	H	5180 ± 1160	-	-	-	-

196a	196b	196c	196d	196e

196f	196g	196h	196i	196j

196k	196l	196m	196n	196o

197a	197b	197c	197d	197e

197f	197g	-	-	-
		-	-	-

Compounds 196e-h possess greater SERT affinity than cocaine, but possess weaker NET/DAT affinities. Compounds 196k, 196n, 196o, and 197c all possess greater DAT affinity than cocaine. 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. Whereas 197c had a 469× increase at SERT, with greater affinity for DAT than cocaine and an equal NET affinity. 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. The consideration that large, bulky C2 substituents would alter the spatial conformation of the tropane ring system by distorting the piperidine portion of the system and thus hamper binding appears to be unfounded.
Benzoylecgonine is the inactive primary metabolite of cocaine generated through hydrolysis of the C2 methyl ester. In vitro binding studies indicate that benzoylecgonine is ~2,200x less potent than cocaine at the dopamine transporter, possibly due to zwitterion formation preventing strong DAT binding. In contrast to in vitro studies, the lack of activity observed in in vivo studies is likely the result of reduced blood–brain barrier penetration than formation of a zwitterion.

[Bioisostere] 2-position carbmethoxy-ester functional replacements

198a	198b	198c	198d

198e	199a	199b	200

Vinylogous 2''β''-position carbmethoxy-ester functional replacements

Structure	S. Singh's alphanumeric assignation	R	Mazindol	DA	Selectivity Uptake/Binding
	-	-	-	-	-
	Cocaine		580 ± 70	570 ± 180	1
	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	PO₂	4850 ± 470	5500 ± 70	1.1

Compounds 201b & 201c were significantly more potent than cocaine while compounds 201a, 201d & 201e were significantly less potent. This finding indicates that the presence of a hydrogen bond acceptor at the 2β position is not absolutely necessary for the creation of high affinity cocaine analogues.

-cocaine	HPBE	-cocaine	C2-ethyl-OSO₂CF₂ cocaine	2- cocaine

''N''-modifications

Compound	S. Singh's alphanumeric assignation	N8-R	Mazindol binding	DA uptake	Selectivity Uptake/Binding
	217	-	10700 ± 1530^ɑ	-	-
		CH₃	280 ± 60 102^ɑ	320 ± 10	1.1
	218	H	303 ± 59^ɑ	-	-
	219a	Bn	668 ± 67^ɑ	-	-
	219b	Ac	3370 ± 1080^ɑ	-	-
	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	1290 ± 80	1970 ± 70	1.5
	220b	SO₂CF₃	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	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 for displacement of WIN 35428

Norcocaine	219a	219b	219c

219d	219e	220a	220b

220c	220d	220e	220f

221a	221b	221c	221d

Tricyclic cocaine analogues

8 to 2 tethered analogues

See N''-front & back bridged phenyltropanes.
Compound S. Singh's
alphanumeric
assignation Mazindol 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 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.

8 to 3 tethered analogues

Structure	Compound	R	X	DA Uptake	5-HT Uptake	NE Uptake	DA/5-HT Selectivity	NE/DA Selectivity
	Cocaine			423 ± 147	155 ± 0.4	108 ± 3.5	2.7	0.26
	-	-	-	-	-	-	-	-
	8a	4-F	CO₂Me	6620 ± 460	335 ± 45	584 ± 163	2.7	0.26
	8b	4-Cl	CO₂Me	853 ± 58	34.3 ± 2.9	208 ± 111	24.8	0.24
	8c	3-Cl	CO₂Me	7780 ± 1580	53.6 ± 17.2	231 ± 44	145	0.03
	8d	4-Br	CO₂Me	495 ± 13	11 ± 3	178 ± 9	45	0.36
	8e	4-I	CO₂Me	764 ± 11	21.9 ± 0.3	213 ± 31	34.9	0.28
	8f	4-CF₃	CO₂Me	N/T	12.6 ± 0.5	1830 ± 211	N/T	N/T
	8g	H	CO₂Me	481 ± 11	1140 ± 70	53 ± 16	0.42	0.11
	8h	4-Me	CO₂Me	649 ± 2	15 ± 0.4	146 ± 28	43.3	0.22
	8i	4-OCH₃	CO₂Me	3130 ± 160	56 ± 4	187 ± 5	55.9	0.06
	8j	4-iPr	CO₂Me	N/T	10.2 ± 0.4	1110 ± 200	N/T	N/T
	8k	3,4-Cl₂	CO₂Me	1920 ± 260	20 ± 1	1000 ± 280	96	0.52
	8l	2,3-Cl₂	CO₂Me	950 ± 107	354 ± 188	1210 ± 358	2.4	1.42
	8m	3,5-Cl₂	CO₂Me	5600 ± 400	437 ± 0.3	4100 ± 500	12.8	0.73
	8n	3,4-F₂	CO₂Me	7440 ± 19	101 ± 8.7	394 ± 98	73.7	0.05
	8o	4-Br-3-Cl	CO₂Me	5420 ± 940	2.3 ± 0.1	459 ± 80	2360	0.08
	8p	3-Cl-4-I	CO₂Me	3140 ± 450	1.8 ± 0.3	272 ± 55	1740	0.09
	8q	2-Cl-4-I	CO₂Me	6640 ± 2080	74 ± 12.2	508 ± 21	89.7	0.08
	8r	3-Cl-4-Me	CO₂Me	>10000	6.4 ± 1.3	198 ± 10	>1560	<0.02
	8s	3,4-Me₂	CO₂Me	N/T	10.1 ± 1.1	659 ± 128	N/T	N/T
	-	-	-	-	-	-	-	-
	8t	1-Naphthyl	CO₂Me	9720 ± 700	121 ± 3	5370 ± 580	80.3	0.55
	8u	2-Naphthyl	CO₂Me	735 ± 235	21 ± 9.9	157 ± 13	35	0.21
	8v	1-Pyrenyl	CO₂Me	9920 ± 906	860 ± 20.6	N/T	11.5	N/T
	8w	9-Phenanthryl	CO₂Me	1640 ± 30	233 ± 44	13000 ± 1300	39.2	0.86

"N/T" = "not tested"

Tropane ring contraction (azabornane) analogues

Structure	S. Singh's alphanumeric assignation	DAT WIN 35428 K_i
		89 ± 4.8
	155a	60400 ± 4800
	155b	96500 ± 42
	155c	5620 ± 390
	155d	18900 ± 1700

6/7 tropane position methoxycocaine & methoxypseudococaine analogues

Compound	S. Singh's alphanumeric assignation	X	K_i Mazindol binding	K_i DA uptake	Selectivity Uptake/Binding
			280 ± 60	320 ± 10	1.1
			10400 ± 300	13800 ± 1500	1.3
	225a	2β, 6β-OCH₃	98000 ± 12000	68000 ± 5000	0.7
	225b	2α, 6β-OCH₃	190000 ± 11000	510000 ± 110000	2.7
	225c	2β, 7β-OCH₃	4200 ± 100	6100 ± 200	1.4
	225d	2α, 7β-OCH₃	45000 ± 5000	110000 ± 4000	2.4
	225e	2α, 7α-OCH₃	54000 ± 3000	200000 ± 70000	3.7

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

Compound	S. Singh's alphanumeric assignation	2β-''R	C2′-R''	IC₅₀
	-	-	-	-
	211a	CH₂OH	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 ± 13^ɑ 34838 ± 796^b

^ɑFor displacement of paroxetine
^bFor displacement of nisoxetine

211a	211b	211c	211d	211e

211f	211g	211h	211i	211j

3''β''-Carbamoyl analogues

Compound	S. Singh's alphanumeric assignation	X	IC₅₀ inhibition of Cocaine binding	IC₅₀ inhibition of DA uptake	Selectivity uptake/binding
			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

See: List of phenyltropanes
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. This may account for PTs increased behavioral stimulation profile over cocaine. 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. Higher pK_ɑs of the tropane nitrogen, decreased aqueous solvation & decreased conformational flexibility added to increased binding affinity.
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.. In addition, it even has been postulated that a crucial role regarding the electron energy imparted via voltage sensitization 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.

3''β''-Alkylphenyltropane & 3''β''-Alkenyl analogues

Compound	S. Singh's alphanumeric assignation	n	IC₅₀ Cocaine binding	IC₅₀ DA uptake	Selectivity uptake/binding
			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

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.

6-Alkyl-3-benzyltropane analogues

Sub-category	a R=H	b R=Me	c R=Et	d R=''n-Pr	e R''=n-Bu	f R=Bn
2β,6α-isomers:	-	-	-	-	-	-
2β,6α-isomers:
2α,6α-isomers:	-	-	-	-	-	-
2α,6α-isomers:
2β,6β-isomers:	-	-	-	-	-	-
2β,6β-isomers:
2α,6β-isomers:	-	-	-	-	-	-
2α,6β-isomers:

Compound	S. Singh's alphanumeric assignation	R	K_i WIN 35428 binding	IC₅₀ DA uptake	Selectivity uptake/binding
	Cocaine		32 ± 5 338 ± 221	405 ± 91 405 ± 91	12.6 1.2
	WIN 35065-2		33 ± 17 314 ± 222	373 ± 10	11.3
	-	-	-	-	-
	-229a	H	33 ± 5	161 ± 100	4.9
	229a	H	91 ± 10	94 ± 26	1.0
	229b	Me	211 ± 23	-	-
	229c	Et	307 ± 28	-	-
	229d	n-Pr	4180 ± 418	-	-
	229e	n-Bu	8580 ± 249	-	-
	229f	Bn	3080 ± 277	-	-
	-	-	-	-	-
	-230a	H	60 ± 6	208 ± 63	3.5
	230a	H	108 ± 14	457 ± 104	4.2
	230b	Me	561 ± 64	-	-
	230c	Et	1150 ± 135	-	-
	230d	n-Pr	7240 ± 376	-	-
	230e	n-Bu	19700 ± 350	-	-
	230f	Bn	7590 ± 53	-	-
	-	-	-	-	-
	231b	Me	57 ± 5	107 ± 36	1.9
	231c	Et	3110 ± 187	-	-
	231d	n-Pr	5850 ± 702	-	-
	231f	Bn	1560 ± 63	-	-
	-	-	-	-	-
	232b	Me	294 ± 29	532 ± 136	1.8
	232c	Et	6210 ± 435	-	-
	232d	n-Pr	57300 ± 3440	-	-
	232f	Bn	3080 ± 277	-	-
	241	Bn	4830 ± 434	-	-

Sub-category	a R=H	b R=Me	c R=Et	d R=''n-Pr	e R''=n-Bu	f R=Bn
6α-isomers:	-	-	-	-	-	-
6α-isomers:
6β-isomers :	-	-	-	-	-	-
6β-isomers :
3β-benzyl derivatives:	-	-	-	-	-	-
3β-benzyl derivatives:
intermediate alkylidene esters:	-	-	-	-	-	-
intermediate alkylidene esters:

N.B. The benzylidene derivatives serve as synthetic intermediates for 6-Alkyl-3-benzyltropanes and have not been assayed for biological activity. Compounds 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

cf. strobamine for a more efficacious compound as like the below.

Structure	alphanumeric assignation	R₁	R₂	hDAT IC₅₀	hSERT IC₅₀	hNET IC₅₀
	-	-	-	-	-	-
	-3a	H	C₆H₅	58,300	6140
	-3a	H	C₆H₅	48,700	6030
	-	-	-	-	-	-
	-3b	H	NH₂
	-3b	H	NH₂
	-	-	-	-	-	-
	-3c	H	CH₃
	-3c	H	CH₃
	-	-	-	-	-	-
	-3d	H	H
	-3d	H	H
	-3e	C₆H₅	C₆H₅	30,000	3650

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

Direct di-hetero-benzene 2,3-fused and thus rigidified cocaine analogs.

Piperidine cocaine-homologues

Compound	S. Singh's alphanumeric assignation	2β-R	IC₅₀
		CO₂CH₃	249 ± 37
	183a	CO₂CH₃	2522 ± 4
	242	H	11589 ± 4
	243	CO₂CH₃	8064 ± 4

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

Cocaine [hapten] analogues

Compound	S. Singh's alphanumeric assignation	2β-R
	394 ^ɑ	CO₂₅CO₂H
	395	CO₂CH₃
	GNE^b including carrier proteins: GNE-FLiC GNE-KLH GNE-BSA
	396	CONH₅CO₂H

^ɑ6--3--8-methyl-8-azabicyclo octane-2-carbonyloxy-hexanoic acid
^b6--3--8-methyl-8-azabicyclo octane-2-carboxamido-hexanoic acid

Compound	S. Singh's alphanumeric assignation	R
	-	-
	401a	CH₃
	401b	₅CO₂H
	401c	CH₂CO₂H
	401d	COCH₂CH₂CO₂H
	401e	H
	401f	CH₂CH₂Br
	385g	₂NHCO₂CONH₂
	-	-
	402a	O₄NHCO₂CO₂N₂C₆H₄
	402b	OH
	402c	O₂
	402d	NH₅CO₂H
	402e	O₄NHCO₂CONH₂
	-	-
	403a	NH₂
	403b	NHCOCH₂Br
	403c	NHCO₃CO₂H
	403d	₃NHCO₂CONH₂

Cocaine haptens that create catalytic anti-bodies require transitional states as affected in vivo. Monoclonal antibodies generated against BSA-coupled 402e accelerated the rate of cocaine hydrolysis by ~23,000x and eliminated the reinforcing effects of cocaine administration in rats.

K1-KLH/BSA	K2-KLH/BSA

Structural/Functional intermediate analogues

Piperidine Analogues

Benztropine (3α-Diphenylmethoxy Tropane) Analogues

Compound	S. Singh's alphanumeric assignation	R	R′	IC₅₀ DAT	IC₅₀ 5-HTT	Selectivity 5-HTT/DAT
				312 ± 1.1	24100 ± 14800	77.2
				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	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	S. Singh's alphanumeric assignation	R	K_i DAT	IC₅₀ 5-HTT	Selectivity uptake/binding
	-	-	-	-	-
	260	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-butyl	20.2 ± 11	650	32.2
	261e	3-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	ethyl	634 ± 23	-	-
	262h	ethyl	57.0 ± 17	-	-
	263	acetyl	2340	4600	2.0
	264	formyl	2020 ± 13	5400	2.7
	265a	tosyl	0%^ɑ	-	-
	265b	mesyl	18%^ɑ	-	-
		CH₂CH=CH₂	-	-	-
		CH₂CH₂CH₂CH₃	-	-	-
		CH₂CH₂NH₂	-	-	-
		CH₂CH₂CH₂CH₂Ph	-	-	-
	266		108 ± 12	130	1.2

^ɑInhibition at 10 μM

Compound	S. Singh's alphanumeric assignation		IC₅₀ DAT	IC₅₀ 5-HTT
	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

The binding of benztropine analogues to the DAT differs significantly from that of cocaine and the phenyltropanes. Benztropines are considered to be "atypical" DAT ligands because they stabilize the DAT in an inward-facing conformation, whereas cocaine and the phenyltropanes stabilize the DAT in an outward-facing conformation. This difference in DAT binding may be responsible for the lack of cocaine-like behavioral effects observed in animal and human studies of the benztropine analogues and other “atypical” DAT inhibitors. Studies of the structure-activity relationships of benztropine have shown that DAT affinity and selectivity over other monoamine transporters is enhanced by 4′,4′-difluorination. Modification of the tropane n-substituent was found to mitigate the anticholinergic effects of benztropine analogues by reducing M1 affinity.

Tropanyl Isoxazoline Analogues

Compound 7a octane-3,5′ allosterically enhances SERT binding of other reuptake ligands. Compound 7a construed as a potentiating allosteric effect at concentrations of 10μM—30μM while exerting an inhibitory orthosteric effect when concentrations reach >30μM and above.
7a is the only known compound to allosterically modulate SERT in such a way within in vitro conditions. 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.
Compound 11a possesses similar effects, but acts on the DAT. Similarly, such peripheral DAT considerations may constitute the difference in affinity, through allosertic occulsion, between cyclopentyl-ruthenium phenyltropane in its difference from the tricarbonyl-chromium

Dihydroimidazoles

See: List of Mazindol analogues
Mazindol is usually considered a non-habituating tetracyclic dopamine reuptake inhibitor.
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 Mazindol to the residues of the MAT binding site, 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.

Local anesthetics (not usually CNS stimulants)

In animal studies, certain of the local anesthetics have displayed residual dopamine reuptake inhibitor properties, although not normally ones that are easily available. These are expected to be more cardiotoxic than phenyltropanes. For example, dimethocaine has behavioral stimulant effects 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. 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.

Name	Other common names
Amylocaine	Stovaine
Articaine	Astracaine, Carticaine, Septanest, Septocaine, Ultracaine, Zorcaine
Benzocaine	Anbesol, Lanacane, Orajel
Bupivacaine	Marcaine, Sensorcaine, Vivacaine
Butacaine	Butyn
Chloroprocaine	Nesacaine
Cinchocaine/Dibucaine	Cincain, Cinchocaine, Nupercainal, Nupercaine, Sovcaine
Cyclomethycaine	Surfacaine, Topocaine
Etidocaine	Duranest
Eucaine	α-eucaine, β-eucaine
Fomocaine
Fotocaine
Hexylcaine	Cyclaine, Osmocaine
Levobupivacaine	Chirocaine
Lidocaine/Lignocaine	Xylocaine, Betacaine
Mepivacaine	Carbocaine, Polocaine
Meprylcaine/Oracaine	Epirocain
Metabutoxycaine	Primacaine
Phenacaine/Holocaine	Holocaine
Piperocaine	Metycaine
Pramocaine/Pramoxine	Pramoxine
Prilocaine	Citanest
Propoxycaine/Ravocaine	Pravocaine, Ranocaine, Blockain
Procaine/Novocaine	Borocaine, Ethocaine
Proparacaine/Alcaine	Alcaine
Quinisocaine	Dimethisoquin
Risocaine	Propaesin, Propazyl, Propylcain
Ropivacaine	Naropin
Tetracaine/Amethocaine	Pontocaine, Dicaine
Trimecaine	Mesdicain, Mesocain, Mesokain