“List of cocaine analogues”的意思、由来-开放百科全书

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:{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#45 Page #969 (45th page of article)] §III. ¶1. Final line. Last sentence.}}

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 (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.{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#94 Page #1,018 (94th page of article) 2nd column, 2nd paragraph.]}}

Analogs sensu stricto

Cocaine Stereoisomers

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)

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

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.{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#58 Page #982 (58th page of article)]}}

meta-substituted benzoylmethylecgonines

ortho-substituted benzoylmethylecgonines

The hydroxylated 2′-OH analogue exhibited a tenfold increase in potency over cocaine.{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#48 Page #972 (48th page of article)] ¶2, Line 10.}}

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.

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.

Benzoyl branch modifications

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 (lacking however, the 2-position carbmethoxy) that is a C1 substituent with a hydroxy group.

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.^[12]

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.^[12]

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,{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50st page of article)] First (left) column, third ¶}} appear to in many cases be unfounded.{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #937 (13th page of article)] Second (right) column, first ¶. Above/before §2}} (examples shown in table of images below)

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.{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50th page of article)] Final ¶ (5th), Second line.}} Whereas 197c had a 469× increase at SERT, with greater affinity for DAT than cocaine & was approximately equipotent to NET.{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#51 Page #975 (51st page of article)] First ¶, first line.}} 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.{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#51 Page #975 (51st page of article)] First ¶, 4th line.}}

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.{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50st page of article)] First (left) column, fourth ¶}}

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.

N-modifications

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

8 to 2 position tropane bridge

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.{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#39 Page #963 (39th page of article)] 2nd (right side) column, 2nd paragraph.}}

Tricyclic cocaine analogues

Tethering the nitrogen 8 tropane position one position further (beyond 2β and crossed-over it / leaving it open as hydrogen and thus possible of having additional unconstrained substitutions there) 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

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;^[21] likely remedying the shallow penetration (for good efficacy) of the latter.

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 (shown twice in different colors, for visibility, above)

6/7 tropane position methoxycocaine & methoxypseudococaine analogues

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

3β-Carbamoyl analogues

Phenyl 3-position linkage substitutions

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.{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#58 Page #982 (58th page of article)] 3rd ¶, lines 2, 5 & 6.}}

6-Alkyl-3-benzyltropane analogues

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

Direct di-hetero-benzene (pyrimidino) 2,3-fused and thus rigidified cocaine analogs.^[27]

Piperidine cocaine-homologues

Cocaine hapten analogues

Cocaine haptens that create catalytic anti-bodies require transitional states as affected in vivo.^[31]^[32]

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)

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.^[37] 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. The alkaloid Meteloidine, found in Datura & Brugmansia, is tentatively also extant in the Australian Erythroxylum species.

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.

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."^[38] 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.

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.^[42] 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."

Benztropine (3α-Diphenylmethoxy Tropane) Analogs

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.^[45]

"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.^[46]^[47]

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.^[46]

This is remarkable considering unmodified (native) benztropine is 60 times more active as an anticholinergic than as a dopaminergic.^[46]

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

Tropanyl Isoxazoline Analogues

8-Aminopentacyclo (σ receptor ligand) Trishomocubane Analogs

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.^[51]

Bicyclic Amine Analogues

Quinuclidine Analogues

Miscellaneous loosely analogous stimulants

Benzoates (Structures with both stimulant & local anesthetic effects)

Organochlorides

Quinolizidines

2,3-Benzodiazepines

Phenethylamines

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)^[53]

Adamantanes

Pyridines

Naphthyridines

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 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)

GBR compounds were derived from the benztropines by replacing their tropane nucleus with a piperazine ring (and therefore constitute being congeners with cocaine).{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#69 Page #993 (69th page of article)] §V. ¶2. Fourth line. First sentence.}} The name "GBR" is derived from its maker Gist-Brocades (now DSM), Netherlands.

GBR compounds are sometimes broadly classed as being, and referred to by the term, "rimcazole analogs"^[56] - for example the compounds: JJC 2-006, JJC 2-010, and JJC 1-059.^[48]

Dihydroimidazoles

Mazindol is usually considered a non-habituating (in humans, and some other mammals, but is habituating for e.g. Beagles{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#87 Page #1,011 (87th page of article)] §VII (7) 1st ¶.}}) 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.{{efn|^[1] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#45 Page #969 (45th page of article)] 2nd (right-side) column 2nd ¶.}}

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,^[58] 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.^[58] 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)

Benzamides

Toxins

See also

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

References

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64. ^{{US patent|6479509}} Patent inventor Frank Ivy Carroll, Assignee: Research Triangle Institute
65. ^[https://patentimages.storage.googleapis.com/US6479509B1/US06479509-20021112-C00016.png U.S. patent US6479509 B1 structures given for submission, 5th compound down in image.]

Analogs sensu stricto