Structural/Functional intermediate analogues List of cocaine analogues

1 structural/functional intermediate analogues

1.1 tropane (non-ecgonine) analogues
1.2 piperidine analogues
1.3 benztropine (3α-diphenylmethoxy tropane) analogs
1.4 tropanyl isoxazoline analogues
1.5 8-aminopentacyclo (σ receptor ligand) trishomocubane analogs
1.6 bicyclic amine analogues
1.7 quinuclidine analogues

structural/functional intermediate analogues
tropane (non-ecgonine) analogues

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

pfbt: zatosetron: tropanserin: bemesetronum:

3-(p-fluorobenzoyloxy)tropane (30% stimulant potency of cocaine & equipotent anaesthetic)
zatosetron (anxiolytic & antinauseant 5ht3 receptor antagonist)
tropanserin (migraine medication, potent & selective 5ht3 antagonist)
bemesetronum (antiemetic, mechanisms related oxytocin function, serotonin d-receptors, cholinoreceptors of muscarinic or nicotinic kind , histamine h1-receptors)


cf. tropisetron

convolamine: phyllalbine: meteloidine:

similarly, many natural tropane alkaloids found in plants of various families have benzoyl tropane structures. including; catuabine, convolamine of convolvulaceae & phyllalbine of euphorbiaceae (phyllanthus discoïdes) families. latter central , peripheral sympathomimetic drug. phyllalbine methylvanillylecgonine tropacocaine, metabolite, cocaine. likewise vanillin hydrolytic degradation product of phyllalbine methyl benzoate cocaine. alkaloid meteloidine, found in datura & brugmansia, tentatively extant in australian erythroxylum species.

butylscopolamine: methylscopolamine: fentonium:

other tropanyl compounds (naturally found or otherwise) begin fall outside spectrum of functional analogues cocaine altogether; having negligible affinity of kind monoamine system. compare example ipratropium, mirisetron, technepine, levomepate or scopolamine & atropine. many of natural varieties being deliriants.

nk-1145: egis-3886: cpd #278 (mono-phenyl benztropine):

the benzoyloxy can replaced other branch formations (terminating in benzene ring) , bridge between still serve create parasympatholytic drug compound causes behavioral stimulation, above: nk-1145 tropine-3β-phenyl ether. deramciclane (egis-3886) camphor derived serotonergic. similar several other kinds of aromatics in structure , being inverse agonist @ 5-ht2c receptor antagonist @ 5-ht2a.

azaprocin: pseudotropinearylether:

azaprocin (a fast onset, short duration opioid analgesic tropane emulating every constituent element shared cocaine; similar how fentanyl overlays methylphenidate, save in case there s additional constituent of phenylethyl tail).
also of note: arene-fluorinated pseudotropinearylethers respect u.s. patent 4,861,889

piperidine analogues

see: list of methylphenidate analogues

many of piperidine analogues of cocaine serve missing link between cocaine structure , of methylphenidate class of drugs. example, dmnpc preserves orientation similar phenyltropanes, structural isomer of methylnaphthidate.

the above depicts 3d structure of above-mentioned methylnaphthidate shown same modeling cocaine derivative win 35428, simple phenyltropane short addition para position. overlay shows closeness of 2 hold respective oxygen , nitrogens in structure (also benzene & cycloalkane ring formations) , meant convey sense of similarity binding mat. correspondingly other monoamine reuptake inhibitors bind dopamine transporter substrate recognition site @ tm loci 1, 7 & 10—12; whereas cocaine & methylphenidate share 1 & 7 places, diverge usual ligand site of latter , instead cohabit 9—11 loci. site-directed mutagenesis techniques have elucidated hydrophobic putative transmembrane regions @ 1 & 7 contain aspartate , serine residues, , carboxyl-group interacts former aspartic acid residue 79 engages cocaine & methylphenidate s protonated nitrogen @ transporter. previous theories of allosteric site cocaine , related compounds not overlap binding site of dopamine less prevalent in light of more recent observations since leut became feasible modeling template.

one rationale denote subjective preference cocaine on methylphenidate in animal habituation & human addiction models has respective difference in entropy of binding: cocaine being —5.6 kcal/mol & methylphenidate being —25.5 kcal/mol (Δs°, measured using [³h]gbr 1278 @ 25 °c)

jz-iv-10 (a modafinil hybrid nocaine. cf. list of modafinil analogues)

nocaine

a recent occurrence among tentative modern folklore has traversed circling of rumors confined likes of universities , popular culture trivia has been cocaine 1 element, or molecule increment of weight or charge etc., away molecular structure of sugar. though such statement false general pretense, there dextrose based super-structure has vaguely similar overlay cocaine benzoyl-beta-d-glucoside.

benzoyl-beta-d-glucoside

benztropine (3α-diphenylmethoxy tropane) analogs


benzatropine (bzt)
difluoropine (o-620), more selective dari cocaine. anticholinergic & antihistamine.
ahn 1-055 same structure benztropine 4′,4′-bisfluorinated.
ga 103 n-phenylpropyl bis-4-fluorobenztropine.
jhw 007 n-(n-butyl)-3α-[bis(4′-fluorophenyl)methoxy]-tropane.

unlike cocaine & phenyltropanes, benztropines & gbr compounds (and, exception cocaine pharmacophore itself, allotropacocaine) among others considered atypical dat re-uptake pump ligands because stabilize dopamine transporter in inward-facing or closed-to-out conformation, contrasts considered cocaine-like affinity dat; instead keep dat stable in open-to-out conformation. means binding of many dopamine reuptake inhibitors atypical of cocaine s method of binding dat , diverges it.

difluoropine not phenyltropane belongs benzatropine family of dris. not confused diaryl -phenyltropanes.

in respects these important because share sar overlap gbr 12909 , related analogs.

sars have shown 4′,4′-difluorination excellent way boost dat activity of benztropine, , gives excellent selectivity on sert , net.

furthermore, replacing n-me with, e.g. n-phenylpropyl helps bring muscarinic activity down same dri affinity.

this remarkable considering unmodified (native) benztropine 60 times more active anticholinergic dopaminergic.

m1 receptor considerations aside, analogues of benztropine class still won t substitute cocaine, , have no propensity elevate locomotor activity.

compound 276



etybenzatropine





compound 277

inhibition @ 10 µm

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



tropanyl isoxazoline analogues










8-aminopentacyclo (σ receptor ligand) trishomocubane analogs

cf. other trishomocubanes such basketane.

interestingly, sigma receptor agonists nanomolar affinity such cm156 have been shown counteract deleterious effects of cocaine when co-administered it. indicative e.g. local anesthetic effect @ sigma site mediating toxicity or otherwise cross on or tie in of cocaine s separate functionalities lowering threshold safety profile.



polycyclic cage molecules: n-substituted 8-aminopentacyclo[5.4.0.0.0.0]undecanes (ahds) & related.

the 3-fph, 14b, has 1.2 ± 0.1 ki (nm ± sem) @ dat.

bicyclic amine analogues

exp-561

quinuclidine analogues

butyltolylquinuclidine

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