List of cocaine analogues
Encyclopedia
This is a list of cocaine
analogues
. A cocaine analogue retains 3β-benzoyloxy or similar functionality unlike phenyltropane
s. Cocaine analogues proper consist of the nine following classes of compounds:
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 phenyltropane stimulant dopamine reuptake inhibitor
ligand
s (such as certain piperidine
s). Many of the stimulant created analogues are of a class of C-2 substituted benzoyloxytropanes.
Analogues with both stimulant
See some of Clarke's contributions
"Difluoropine" is not a phenyltropane but actually belongs to the benztropine
family of DRIs.
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 affinty.
This is remarkable considering unmodified (native) 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.
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.
Common analogues to prototypical D
RA
s:
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
analogues
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
. A cocaine analogue retains 3β-benzoyloxy or similar functionality unlike phenyltropane
Phenyltropane
Phenyltropanes were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, they are not the only researchers that have prepared these...
s. Cocaine analogues proper consist of 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-subtituted cocaines
- 6-alkyl-3-benzyl tropanes
- piperidine homologues of cocaine
The term may also be loosely used to refer to drugs manufactured from cocaine or having their basis as a total synthesis
Total synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...
of cocaine, but modified to alter their effect & QSAR. These include both intracellular sodium channel blocker anesthetics and phenyltropane stimulant dopamine reuptake inhibitor
Dopamine reuptake inhibitor
A dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s (such as certain piperidine
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
s). Many of the stimulant created analogues are of a class of C-2 substituted benzoyloxytropanes.
Cocaine Stereoisomers
| Stereoisomer | IC50 IC50 The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance is needed to inhibit a given biological process by half... (nM) |
|---|---|
| R-cocaine Cocaine Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic... |
102 |
| R-pseudococaine | 15800 |
| R-allococaine | 6160 |
| R-allopseudococaine | 28500 |
| S-cocaine | 15800 |
| S-pseudococaine | 22500 |
| S-allococaine | 9820 |
| S-allopseudococaine | 67700 |
Benzoyl- branch cleavage substitutions (excluding the exhaustive phenyl- group) & active transesterification metabolites of cocaine
- CocaethyleneCocaethyleneCocaethylene is the ethyl ester of benzoylecgonine. It is structurally similar to cocaine, which is the methyl ester of benzoylecgonine. Cocaethylene is formed in vivo when cocaine and ethyl alcohol have been ingested simultaneously....
- 2'-Acetoxycocaine2'-Acetoxycocaine2'-Acetoxycocaine is a cocaine analog, with a quicker effect onset than cocaine. The acetoxy branch renders the molecule a QSAR of a 4-fold increase over cocaine in its binding potency for the dopamine transporter & a 35-fold enhanced affinity for the norepinephrine transporter. It also has a...
- 4'-Fluorococaine4'-Fluorococaine4'-Fluorococaine is a tropane derivative drug which is a synthetic analogue of cocaine. Unlike related compounds such as the corresponding 4'-fluorophenyltropane derivative CFT and the 2'-hydroxy analogue salicylmethylecgonine, 4'-fluorococaine has only around the same potency as cocaine as an...
- BenzoylthiomethylecgonineBenzoylthiomethylecgonineBenzoylthiomethylecgonine is a cocaine analog which includes a sulfur in replacement of an oxygen on the single bonded benzoyl ester, resulting in lower electronegativity than the parent compound....
- SalicylmethylecgonineSalicylmethylecgonineSalicylmethylecgonine, is a tropane derivative drug which is both a synthetic analogue and a possible active metabolite of cocaine...
- MethylvanillylecgonineMethylvanillylecgonineMethylvanillylecgonine or vanillylmethylecgonine is a cocaine analog and metabolite of cocaine found in human urine...
- Isothiocyanatobenzoylecgonine methyl ester(R)-p-Isothiocyanatobenzoylecgonine methyl ester-p-Isothiocyanatobenzoylecgonine methyl ester is a cocaine analogue and irreversible binding inhibitor of the cocaine receptor, as well as irreversible blocker of dopamine uptake by DAT...
Miscellaneous stimulant analogues
Analogues with both stimulantStimulantStimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
& local anestheticLocal anestheticA local anesthetic is a drug that causes reversible local anesthesia, generally for the aim of having local analgesic effect, that is, inducing absence of pain sensation, although other local senses are often affected as well...
effects
- Dimethocaine/Larocaine (DMC)DimethocaineDimethocaine, also known as larocaine, is a local anesthetic with stimulant properties that some studies have shown to be half the potency of cocaine. Anecdotal user reports indicate little euphoria and only mild stimulating effects, with many users failing to perceive any recreational effects...
- 3-(p-Fluorobenzoyloxy)tropane (30% stimulant potency of cocaine & equipotent as an anaesthetic)
See some of Clarke's contributions
Phenyltropanes series (excluding all other benzoyl- branch substitutions)
See: List of phenyltropanesPiperidine Analogues
- Methylnaphthidate (HDMP-28)HDMP-28HDMP-28 or methylnaphthidate is a piperidine based stimulant drug, closely related to methylphenidate, but with the phenyl ring replaced by naphthalene...
- Nocaine
- DMNPC
- JZ-IV-10JZ-IV-10JZ-IV-10 is a piperidine derivative related to nocaine which is a highly potent triple reuptake inhibitor . The eugeroic modafinil, was used as a lead to fuel these compounds' discovery . Although it turns out that the QSAR of the pharmacophoric elements do not appear to be strongly similar...
- MethylphenidateMethylphenidateMethylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
Benztropine Analogs
- BenztropineBenztropineBenzatropine , also known as benztropine , is an anticholinergic marketed under the trade name Cogentin which is used in the treatment of Parkinson's disease, parkinsonism, akathisia, and dystonia.- Indications :...
- DifluoropineDifluoropine--2β-Carbomethoxy-3α-tropane is a stimulant drug synthesised from tropinone, which acts as a potent and selective dopamine reuptake inhibitor...
(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-(n-butyl)-3α-[bis(4'-fluorophenyl)methoxy]-tropane
"Difluoropine" is not a phenyltropane but actually belongs to the benztropine
Benztropine
Benzatropine , also known as benztropine , is an anticholinergic marketed under the trade name Cogentin which is used in the treatment of Parkinson's disease, parkinsonism, akathisia, and dystonia.- Indications :...
family of DRIs.
In certain respects these are important because they share SAR overlap with GBR 12909
Vanoxerine
Vanoxerine is a piperazine derivative which is a potent and selective DRI. GBR-12909 binds to the target site on the DAT ~ 500 times more strongly than cocaine, but simultaneously inhibits the release of dopamine...
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 affinty.
This is remarkable considering unmodified (native) 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.
Phenethylamines
- Methylenedioxypyrovalerone
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.
Local anesthetics (not usually CNS stimulants)
Note: Certain of the local anesthetics still have residual DRI 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 (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.
|
Mepivacaine Mepivacaine is a local anesthetic of the amide type. Mepivacaine has a reasonably rapid onset and medium duration of action and is marketed under various trade names including Carbocaine and Polocaine.Mepivacaine became available in the United States in the 1960s.Mepivacaine is used in any... (Carbocaine, Polocaine) Meprylcaine Meprylcaine is a local anesthetic.... Metabutoxycaine Metabutoxycaine, marketed under the trade name Primacaine, is a local anesthetic. It is used in dentistry.... (Primacaine) Piperocaine Piperocaine is a local anesthetic drug developed in the 1920s and used as its hydrochloride salt for infiltration and nerve blocks.-External links:*... (Metycaine) Prilocaine Prilocaine is a local anesthetic of the amino amide type first prepared by Claes Tegner and Nils Lofgren. In its injectable form , it is often used in dentistry. It is also often combined with lidocaine as a preparation for dermal anesthesia , for treatment of conditions like paresthesia... Propoxycaine Propoxycaine is a local anesthetic.... Procaine Procaine is a local anesthetic drug of the amino ester group. It is used primarily to reduce the pain of intramuscular injection of penicillin, and it was also used in dentistry. Owing to the ubiquity of the trade name Novocain, in some regions procaine is referred to generically as novocaine... (Novocain) Risocaine Risocaine is a local anesthetic.... Ropivacaine Ropivacaine is a local anaesthetic drug belonging to the amino amide group. The name ropivacaine refers to both the racemate and the marketed S-enantiomer... Tetracaine Tetracaine is a potent local anesthetic of the ester group... (Pontocaine) Trimecaine Trimecaine is an organic compound used as a local anesthetic and cardial antiarrhythmic. It is white crystalline powder readily soluble in water and ethanol... |
See also
- DopaminergicDopaminergicDopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
s - Federal Analog ActFederal Analog ActThe Federal Analog Act, , is a controversial section of the United States Controlled Substances Act which allowed any chemical "substantially similar" to a controlled substance listed in Schedule I or II to be treated as if it were also listed in those schedules, but only if intended for human...
- PharmacophorePharmacophorethumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
- PharmacopoeiaPharmacopoeiaPharmacopoeia, pharmacopeia, or pharmacopoea, , in its modern technical sense, is a book containing directions for the identification of samples and the preparation of compound medicines, and published by the authority of a government or a medical or pharmaceutical society.In a broader sense it is...
- PharmacokineticsPharmacokineticsPharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
Common analogues to prototypical D
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
RA
Releasing agent
A releasing agent , or simply releaser, is a drug that induces the release of a neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs use neurotransmitter release to exert their psychological and...
s:
- Substituted amphetamineSubstituted amphetamineSubstituted amphetamines are a chemical class of stimulants, entactogens, hallucinogens, and other drugs. They feature a phenethylamine core with a methyl group attached to the alpha carbon resulting in amphetamine, along with additional substitutions...
s - Substituted cathinoneSubstituted cathinoneSubstituted cathinones, which include some stimulants and entactogens, are derivatives of cathinone. They feature a phenethylamine core with an alkyl group attached to the alpha carbon, and a ketone group attached to the beta carbon, along with additional substitutions...
s - Substituted phenethylamineSubstituted phenethylamineThe substituted phenethylamines are chemical compounds with the 2-phenethylamine chemical structure modified at the phenyl ring, sidechain, and/or amino group. Some of them are psychoactive drugs, including stimulants, psychedelics, opioids, and entactogens, which exert their effects primarily...
s - Substituted methylenedioxyphenethylamines