List of cocaine analogues

This is a list of cocaine analogues. A cocaine analogue is a 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 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

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

Stereoisomer	S. Singh's alphanumeric assignation	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

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 carbomethoxy 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)

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

''para''-substituted benzoylmethylecgonines

Structure	S. Singh's alphanumeric assignation	4′=R	DAT WIN 35428	5-HTT Paroxetine	NET Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
		H	249 ± 37	615 ± 120	2500 ± 70	2.5	10.0
non-benzoyloxy analogue comparative ligands	11b	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
		F	-	-	-	-	-
		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.

''meta''-substituted benzoylmethylecgonines

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

^ɑIC₅₀ value for displacement of cocaine
''ortho''-substituted benzoylmethylecgonines

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

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

^ɑIC₅₀ value for displacement of cocaine
manifold benzoyloxy phenyl-substitutions

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.
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 ; yet oxycodone's intermediates in its synthesis from codeine are: ⅓ the potency of codeine ; 0.13 that of morphine in rats and less in mice ; with the final possible stand alone intermediate compound between codeine & oxycodone being at most 150% to 200% that of codeine.

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	-	-	-	-	-

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.

Structure	S. Singh's alphanumeric assignation	C=R	DAT Cocaine	5-HTT Paroxetine	NET Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	187	1-naphthalene	742 ± 48	-	-	-	-
	188	2-naphthalene	327 ± 63	-	-	-	-

Benzoyl 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.

C1-tropane-ring hydrogen—substitutions

cf. hydroxytropacocaine for a natural alkaloid that is a C1 substituent with a hydroxy group.

Structure	Trivial name	R	K_i @ DAT	K_i @ SERT	K_i @ NET	σ₁ affinity K_i	σ₂ affinity K_i	IC₅₀ Na+ inhibition ^c	LogP
	-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.

2''β''-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, appear to in many cases be unfounded.
.
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 & was approximately equipotent to NET. 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.

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	-	-	-	-

[Bioisostere] 2-position carbmethoxy-ester functional replacements

Benzoylecgonine, i.e. compound 197e, has an extreme loss in potency as displayed by in vitro methodologies for determining binding efficacy and is posited to be due possibly to zwitterion formation.

Structure	S. Singh's alphanumeric assignation	R	Mazindol	DA	Selectivity Uptake/Binding
			580 ± 70	570 ± 180	1.0
	-	-	-	-	-
	198a	H	520 ± 40	260 ± 70	0.5
	198b	CO₂Et	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
	-	-	-	-	-

Structure	S. Singh's alphanumeric assignation	R	Mazindol	DA	Selectivity Uptake/Binding
	-	-	-	-	-
	199a	βCO₂Et	710 ± 150	1060 ± 340	1.5
	199b	αCO₂Et	5830 ± 630	8460 ± 620	1.4

Structure	S. Singh's alphanumeric assignation	R	Mazindol	DA	Selectivity Uptake/Binding
	200		880 ± 350	400 ± 140	0.4

Vinylogous 2''β''-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.
File:D5-phenyl cocaine.svg|thumb|-cocaine: reagent analogue, as above thumbnail of similar compound: rendered from its cocaine parent by replacing a cluster of several adjacent hydrogens with deuterium, in an equivalent but localized spread or cluster.

Structure	S. Singh's alphanumeric assignation	R	Mazindol	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	PO₂	4850 ± 470	5500 ± 70	1.1

''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
Bridged (''N''-constrained/tethered) tropane-fused cocaine analogues

8 to 2 position tropane bridge

Compound	S. Singh's alphanumeric assignation	R	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.

Tricyclic cocaine analogues

Tethering the nitrogen 8 tropane position one position further and linking all the way across to the 3β aryl, replacing it; yields an expansive front-bridged structure to create a structurally tricyclic series of cocaine analogues.

8 to 3 position

Compound	X	Y	R	SERT K_i	DAT K_i	NET K_i
1	Cl	Cl	CH₂OCOMe	1.6	1870	638
2	Br	Cl	CO₂Me	2.3	5420	459
3	I	Cl	CH₂OCOPh	0.06	>10K	>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; likely remedying the shallow penetration of the latter.
5-benzoatic & 6-benzoatic
Comparison of tropane ring versus the norbornane in overlay, with contrast of benzoyl branch in its configuration of how it lays extended out from body of either main ring type

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	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 ± 13^ɑ 34838 ± 796^b

^ɑFor displacement of paroxetine
^bFor displacement of nisoxetine
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

: A structural analogue of cocaine with omitted -COO- linkage – a parent compound of many MAT ligands; those of the phenyltropane class.
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

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.

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

6-Alkyl-3-benzyltropane analogues

Compound	S. Singh's alphanumeric assignation	R	K_i WIN 35428 binding	IC₅₀ DA uptake	Selectivity uptake/binding
			32 ± 5 338 ± 221	405 ± 91 405 ± 91	12.6 1.2
	11a		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: 237a—f	-	-	-	-	-	-
6α-isomers: 237a—f
6β-isomers : 238a—f	-	-	-	-	-	-
6β-isomers : 238a—f
3β-benzyl derivatives: 239a—f	-	-	-	-	-	-
3β-benzyl derivatives: 239a—f
intermediate alkylidene esters: 240a—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

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	NA
	-3a	H	C₆H₅	48,700	6030	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	3650	NA

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

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

Piperidine cocaine-homologues

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

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

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	O₄NHCO₂CO₂...2,3-dihydro-1H-isoindole-1,3-dione
	402b	OH
	402c	O₂...1,4-xylene...NH₂
	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.

Compound	Name
	-
	K1-KLH/BSA
	-
	K2-KLH/BSA

Structural/Functional intermediate analogues

Piperidine Analogues

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. 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
Difluoropine, 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 N--3α--tropane.

Unlike cocaine & phenyltropanes, the benztropines & GBR compounds 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.
"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.
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.
This is remarkable considering unmodified benztropine is 60 times more active as an anticholinergic than as a dopaminergic.
M1 receptor considerations aside, analogues of this benztropine class still won't substitute for cocaine, and have no propensity to elevate locomotor activity.

Compound	S. Singh's alphanumeric assignation	R	R′	K_i WIN 35428 binding	IC₅₀ DA uptake	Selectivity uptake/binding
				388 ± 47	-	-
				11.6 ± 31	-	-
	-	-	-	-	-	-
		H	H	118 ± 9	403 ± 115	3.4
	249a	4′-F	H	32.2 ± 10	48	1.5
	249b	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

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

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	Ts	0%^ɑ	-	-
	265b	Ms	18%^ɑ	-	-
		CH₂CH=CH₂	-	-	-
		CH₂CH₂CH₂CH₃	-	-	-
		CH₂CH₂NH₂	-	-	-
		CH₂CH₂CH₂CH₂Ph	-	-	-
	266		108 ± 12	130	1.2

^ɑInhibition at 10 μM
; a di-para-fluoro benztropine, and hybrid between benzatropine & difluoropine.

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

Tropanyl Isoxazoline Analogues

Compound	Name	-	-	-
-
-	4a	4c	5a	5c
-
-	6a	6b	6c	7a
-
-	7b	7c	8a	8b
-
-	8c	9a	9b	9c
-				-
-	9c	10a	10b	10c
-
-	11a	11b	12a	12b

8-Aminopentacyclo (σ receptor ligand) [Trishomocubane] Analogs

cf. other trishomocubanes such as basketane.
Sigma receptor agonists with nanomolar affinity such as CM156 have been shown to counteract the deleterious effects of cocaine when co-administered with it. Indicative that e.g. the local anesthetic effect at the sigma site mediating the toxicity or otherwise a cross over or tie in of cocaine's separate functionalities lowering threshold to its safety profile.
Polycyclic cage molecules: N-substituted 8-aminopentacycloundecanes & related.
The 3-FPh, 14b, has 1.2 ± 0.1 K_i @ DAT.

Bicyclic Amine Analogues

EXP-561

Quinuclidine Analogues

Butyltolylquinuclidine

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.
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)

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. 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, Septanest, Septocaine, Ultracaine, Zorcaine
Benzocaine
Bupivacaine	Marcaine, Sensorcaine, Vivacaine
Butacaine
Carticaine
Chloroprocaine	Nesacaine
Cinchocaine/Dibucaine	Cincain, Cinchocaine, Nupercainal, Nupercaine, Sovcaine
Cyclomethycaine	Surfacaine, Topocaine
Etidocaine
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
Piperocaine	Metycaine
Pramocaine/Pramoxine
Prilocaine	Citanest
Propoxycaine/Ravocaine
Procaine/Novocaine	Borocaine, Ethocaine
Proparacaine/Alcaine
Quinisocaine	Dimethisoquin
Risocaine
Ropivacaine	Naropin
Tetracaine/Amethocaine	Pontocaine, Dicaine
Trimecaine	Mesdicain, Mesocain, Mesokain

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