Arylcyclohexylamine

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Phencyclidine, the prototypal arylcyclohexylamine derivative.

Arylcyclohexylamines, also known as arylcyclohexamines or arylcyclohexanamines, are a chemical class of pharmaceutical, designer, and experimental drugs.

History

Phencyclidine (PCP) is believed to be the first arylcyclohexylamine with recognized anesthetic properties, but several arylcyclohexylamines were described before PCP in the scientific literature, beginning with PCA (1-phenylcyclohexan-1-amine) the synthesis of which was first published in 1907. PCE was reported in 1953 and PCMo in 1954, with the latter compound described as a potent sedative.[1] Arylcyclohexylamine anesthetics were intensively investigated at Parke-Davis, beginning with the 1956 synthesis of phencyclidine and later the related compound ketamine.[1] The 1970s saw the debut of these compounds, especially PCP and its analogues, as illicitly used recreational drugs due to their dissociative hallucinogenic and euphoriant effects. Since, the class has been expanded by scientific research into stimulant, analgesic, and neuroprotective agents, and also by clandestine chemists in search of novel recreational drugs.[2][3][4]

Structure

General structure of arylcyclohexylamines

An arylcyclohexylamine is composed of a cyclohexylamine unit with an aryl moiety attachment. The aryl group is positioned geminal to the amine. In the simplest cases, the aryl moiety is typically a phenyl ring, sometimes with additional substitution. The amine is usually not primary; secondary amines such as methylamino or ethylamino, or tertiary cycloalkylamines such as piperidino and pyrrolidino, are the most commonly encountered N-substituents.

Pharmacology

Arylcyclohexylamines varyingly possess NMDA receptor antagonistic,[5][6] dopamine reuptake inhibitory,[7] and μ-opioid receptor agonistic[8] properties. Additionally, σ receptor agonistic,[9] nACh receptor antagonistic,[10] and D2 receptor agonistic[11] actions have been reported for some of these agents. Antagonism of the NMDA receptor confers anesthetic, anticonvulsant, neuroprotective, and dissociative effects; blockade of the dopamine transporter mediates stimulant and euphoriant effects as well as psychosis in high amounts; and activation of the μ-opioid receptor causes analgesic and euphoriant effects. Stimulation of the σ and D2 receptors may also contribute to hallucinogenic and psychotomimetic effects.[11]

These are versatile agents with a wide range of possible pharmacological activities depending on the extent and range to which chemical modifications are implemented.[12][13][14][15][16][17][18][19][20] The various choice of substitutions that are made allows for "fine-tuning" of the pharmacological profile that results. As examples, BTCP is a selective dopamine reuptake inhibitor,[7] PCP is primarily an NMDA antagonist,[5] and BDPC is a potent μ-opioid agonist,[21] while PRE-084 is a selective sigma receptor agonist.[22] Thus, radically different pharmacology is possible through different structural combinations.

List of arylcyclohexylamines

Structure Compound Aryl Substituent N Group Cyclohexyl ring
PCA[23] Phenyl NH2 -
PCM[23] Phenyl Methylamino -
Eticyclidine Phenyl Ethylamino -
PCPr [24] Phenyl n-Propylamino -
PCiP Phenyl Isopropylamino -
PCAL [25] Phenyl Allylamino -
PCBu Phenyl n-Butylamino -
PCEOH Phenyl Hydroxyethylamino -
PCMEA[26] Phenyl Methoxyethylamino -
PCEEA Phenyl Ethoxyethylamino -
PCMPA Phenyl Methoxypropylamino -
PCDM[23] Phenyl Dimethylamino -
Dieticyclidine Phenyl Diethylamino -
2-HO-PCP[5] Phenyl Piperidine 2-Hydroxy
2-Me-PCP[27] Phenyl Piperidine 2-Methyl
2-MeO-PCP[28] Phenyl Piperidine 2-Methoxy
2-Keto-PCP Phenyl Piperidine 2-Keto
Eticyclidone ("O-PCE") Phenyl Ethylamino 2-Keto
2-Keto-PCPr Phenyl n-Propylamino 2-Keto
4-Methyl-PCP Phenyl Piperidine 4-Methyl
4-Keto-PCP Phenyl Piperidine 4-Keto
2'-Cl-PCP o-Chlorophenyl Piperidine -
2'-MeO-PCP o-Methoxyphenyl Piperidine -
3'-F-PCP[29] m-Fluorophenyl Piperidine -
3'-Me-PCP[30] m-Tolyl Piperidine -
3'-Me-PCPy m-Tolyl Pyrrolidine -
3'-NH2-PCP m-Aminophenyl Piperidine -
3'-HO-PCP m-Hydroxyphenyl Piperidine -
3'-MeO-PCP m-Methoxyphenyl Piperidine -
3',4'-MD-PCP 3,4-Methylenedioxyphenyl Piperidine -
3'-MeO-PCE m-Methoxyphenyl Ethylamino -
3'-HO-PCE m-Hydroxyphenyl Ethylamino -
3'-MeO-PCPr m-Methoxyphenyl n-Propylamino -
3'-HO-PCPr m-Hydroxyphenyl n-Propylamino -
3',4'-MD-PCPr 3,4-Methylenedioxyphenyl n-Propylamino -
3'-MeO-PCPy[30] m-Methoxyphenyl Pyrrolidine -
4'-HO-PCP p-Hydroxyphenyl Piperidine -
Methoxydine (4'-MeO-PCP) p-Methoxyphenyl Piperidine -
4'-MeO-PCE p-Methoxyphenyl Ethylamino -
4'-F-PCP[29] p-Fluorophenyl Piperidine -
4'-F-PCPy p-Fluorophenyl Pyrrolidine -
Arketamine o-Chlorophenyl Methylamino 2-Keto
Deschloroketamine Phenyl Methylamino 2-Keto
Esketamine o-Chlorophenyl Methylamino 2-Keto
Ketamine o-Chlorophenyl Methylamino 2-Keto
Hydroxynorketamine o-Chlorophenyl NH2 2-Keto, 6-Hydroxy
Ethketamine o-Chlorophenyl Ethylamino 2-Keto
NPNK o-Chlorophenyl n-Propylamino 2-Keto
Methoxyketamine o-Methoxyphenyl Methylamino 2-Keto
oMDCK o-Tolyl Methylamino 2-Keto
mMDCK m-Tolyl Methylamino 2-Keto
meta-Ketamine m-Chlorophenyl Methylamino 2-Keto
iso-Ketamine o-Chlorophenyl Methylamino 4-Keto
2-Fluorodeschloroketamine o-Fluorophenyl Methylamino 2-Keto
3-Fluorodeschloroketamine m-Fluorophenyl Methylamino 2-Keto
Bromoketamine o-Bromophenyl Methylamino 2-Keto
TFMDCK o-Trifluoromethylphenyl Methylamino 2-Keto
SN 35210 [31] o-Chlorophenyl Carbomethoxybutylamino 2-Keto
Methoxetamine m-Methoxyphenyl Ethylamino 2-Keto
Methoxmetamine m-Methoxyphenyl Methylamino 2-Keto
MXPr m-Methoxyphenyl n-Propylamino 2-Keto
HXE m-Hydroxyphenyl Ethylamino 2-Keto
HXM m-Hydroxyphenyl Methylamino 2-Keto
FXE m-Fluorophenyl Ethylamino 2-Keto
Phencyclidine (PCP) Phenyl Piperidine -
PC3MP Phenyl 3-Methylpiperidine -
PC4MP Phenyl 4-Methylpiperidine -
Rolicyclidine (PCPy) Phenyl Pyrrolidine -
PCDMPy Phenyl 3,3-Dimethylpyrrolidine -
PCMo Phenyl Morpholine -
Methoxy-PCM[6] (2'-MeO-PCMo) o-Methoxyphenyl Morpholine -
3'-MeO-PCMo m-Methoxyphenyl Morpholine -
4'-MeO-PCMo p-Methoxyphenyl Morpholine -
Methyl-PCM[32] (4'-Me-PCMo) p-Tolyl Morpholine -
Hydroxy-methyl-PCM 2-Methyl-4-hydroxyphenyl Morpholine -
PYCP [33] 2-Pyridinyl Piperidine -
TCM 2-Thienyl Methylamino -
TCE 2-Thienyl Ethylamino -
TCPr [34] 2-Thienyl Propylamino -
Tenocyclidine (TCP) 2-Thienyl Piperidine -
TCPy 2-Thienyl Pyrrolidine -
Tiletamine 2-Thienyl Ethylamino 2-Keto
Gacyclidine 2-Thienyl Piperidine 2-Methyl
BDPC p-Bromophenyl Dimethylamino 4-Phenethyl-4-hydroxy
C-8813 p-Bromophenyl Dimethylamino 4-(thiophen-2-yl)ethyl-4-hydroxy
Dimetamine [35] p-Tolyl Dimethylamino 4-Keto
3''-OH-2'-Me-PCP [36] o-Tolyl 3-Hydroxypiperidine -
4''-Ph-4''-OH-PCP [37] Phenyl 4-Phenyl-4-hydroxypiperidine -
BTCP[38] Benzothiophen-2-yl Piperidine -
BTCPy[39] Benzothiophen-2-yl Pyrrolidine -
PRE-084 Phenyl Morpholinylethylcarboxylate -

Other cycloalkane ring sizes have been experimented with than just purely thinking in terms of the cyclohexylamine. The cyclopentyl homologue of PCP is active with around 1/10th the potency, while the cycloheptyl and cyclooctyl derivatives are inactive. The requisite cycloalkylketone is reacted with PhMgBr; 3° alcohol is then reacted with NaN3; azide then reduced with LAH. Then in the final step the piperidine ring is constructed with 1-5-dibromo-pentane.[40]

Rigid

Conformationally constrained analogs have also been prepared and researched by Morieti et al.[41]

References

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External links

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