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. PCP itself was discovered in 1926 but not researched by the pharmaceutical industry until the 1950s. PCE was reported in 1953 and PCMo (4-(1-phenyl-cyclohexyl)-morpholine see chart below for figure) in 1954, with PCMo described as a potent sedative. Arylcyclohexylamine anesthetics were intensively investigated at Parke-Davis, beginning with the 1956 studies of PCP and later the related compound ketamine. 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 that time, 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.
Structure
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 methylamine or ethylamine, or tertiary cycloalkylamines such as piperidine and pyrrolidine, are the most commonly encountered N-substituents.
Pharmacology Arylcyclohexylamines varyingly possess NMDA receptor antagonistic, dopamine reuptake inhibitory, and μ-opioid receptor agonistic properties. Additionally, σ receptor agonistic, nACh receptor antagonistic, and D2 receptor agonistic 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.
These are versatile agents with a wide range of possible pharmacological activities depending on the extent and range to which chemical modifications are implemented. 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, PCP is primarily an NMDA antagonist, and BDPC is a potent μ-opioid agonist, while PRE-084 is a selective sigma receptor agonist. Thus, radically different pharmacology is possible through different structural combinations.
Notes on numbering PCP itself is composed of three six-membered rings, which can each be substituted by a variety of groups. These are traditionally numbered in the older research as first the cyclohexyl ring, then the phenyl, and finally the piperidine ring, with the different rings represented by prime notation (') next to the number. For instance, 4-methyl-PCP, 4'-methyl-PCP and 4''-methyl-PCP are all known compounds, with similar activity but quite different potencies.
However, since the widespread sale of these compounds as grey-market designer drugs, nearly all such compounds that have come to prominence either have a bare cyclohexyl ring or a 2-ketocyclohexyl ring, while the piperidine is replaced by a variety of alkyl or cycloalkyl amines and most substitution has taken place on the phenyl ring. Consequently, it is common for widely used phenyl substituted analogues such as 3'-MeO-PCP and 3'-MeO-PCE to be referred to as 3-MeO-PCP and 3-MeO-PCE without the prime, even though this is technically incorrect and could lead to confusion.
List of arylcyclohexylamines
Structures Compound Aryl Substituent N Group Cyclohexyl ring CAS # PCA Phenyl NH2 - 1934-71-0 PCM Phenyl Methylamino - 2201-16-3 Eticyclidine Phenyl Ethylamino - 2201-15-2 PCPr Phenyl n-Propylamino - 18949-81-0 PCiP Phenyl Isopropylamino - 1195-42-2 PCAL Phenyl Allylamino - 2185-95-7 PCBu Phenyl n-Butylamino - 73166-29-7 PCEOH Phenyl Hydroxyethylamino - 2201-22-1 PCMEA Phenyl Methoxyethylamino - 2201-57-2 PCEEA Phenyl Ethoxyethylamino - 1072895-05-6 PCMPA Phenyl Methoxypropylamino - 2201-58-3 PCDM Phenyl Dimethylamino - 2201-17-4 Dieticyclidine Phenyl Diethylamino - 2201-19-6 2-HO-PCP Phenyl Piperidine 2-Hydroxy 94852-58-1 2-Me-PCP Phenyl Piperidine 2-Methyl 59397-29-4 2-MeO-PCP Phenyl Piperidine 2-Methoxy 78636-34-7 2-Keto-PCP ("O-PCP") Phenyl Piperidine 2-Keto 101688-16-8 Eticyclidone ("O-PCE") Phenyl Ethylamino 2-Keto 6740-82-5 2-Keto-PCPr ("O-PCPr") Phenyl n-Propylamino 2-Keto 4-Methyl-PCP Phenyl Piperidine 4-Methyl 19420-52-1 4-Keto-PCP Phenyl Piperidine 4-Keto 65620-13-5 2'-Cl-PCP o-Chlorophenyl Piperidine - 2201-31-2 2'-Cl-O-PCP o-Chlorophenyl Piperidine 2-Keto 3'-Cl-PCP m-Chlorophenyl Piperidine - 2201-32-3 2'-MeO-PCP o-Methoxyphenyl Piperidine - 2201-34-5 3'-F-PCP m-Fluorophenyl Piperidine - 89156-99-0 3'-Me-PCP m-Tolyl Piperidine - 2201-30-1 3'-Me-PCPy m-Tolyl Pyrrolidine - 1622348-63-3 3'-NH2-PCP m-Aminophenyl Piperidine - 72242-00-3 3'-HO-PCP m-Hydroxyphenyl Piperidine - 79787-43-2 3'-MeO-PCP m-Methoxyphenyl Piperidine - 72242-03-6 3-EtO-PCP m-Ethoxyphenyl Piperidine - 3',4'-MD-PCP 3,4-Methylenedioxyphenyl Piperidine - 3'-Me-PCE m-Tolyl Ethylamino - 2201-64-1 3'-MeO-PCE m-Methoxyphenyl Ethylamino - 1364933-80-1 3'-HO-PCE m-Hydroxyphenyl Ethylamino - 3-Cl-PCE m-Chloro Ethylamino - 3'-MeO-PCPr m-Methoxyphenyl n-Propylamino - 1364933-81-2 3'-HO-PCPr m-Hydroxyphenyl n-Propylamino - 3',4'-MD-PCPr 3,4-Methylenedioxyphenyl n-Propylamino - 3'-MeO-PCPy m-Methoxyphenyl Pyrrolidine - 1364933-79-8 3-F-PCiPr m-Fluorophenyl i-Propylamino - 4'-HO-PCP p-Hydroxyphenyl Piperidine - 66568-88-5 Methoxydine (4'-MeO-PCP) p-Methoxyphenyl Piperidine - 2201-35-6 4'-MeO-PCE p-Methoxyphenyl Ethylamino - 4'-F-PCP p-Fluorophenyl Piperidine - 22904-99-0 4'-F-PCPy p-Fluorophenyl Pyrrolidine - Arketamine o-Chlorophenyl Methylamino 2-Keto 33643-49-1 Deschloroketamine Phenyl Methylamino 2-Keto 7063-30-1 Esketamine o-Chlorophenyl Methylamino 2-Keto 33643-46-8 Ketamine o-Chlorophenyl Methylamino 2-Keto 6740-88-1 Hydroxynorketamine o-Chlorophenyl NH2 2-Keto, 6-Hydroxy 81395-70-2 Ethketamine o-Chlorophenyl Ethylamino 2-Keto 1354634-10-8 NPNK o-Chlorophenyl n-Propylamino 2-Keto 2749326-65-4 A-NK o-Chlorophenyl pent-4-ynylamino 2-Keto Methoxyketamine o-Methoxyphenyl Methylamino 2-Keto 7063-51-6 2-MeO-NEK o-Methoxyphenyl Ethylamino 2-Keto oMDCK o-Tolyl Methylamino 2-Keto 7063-37-8 mMDCK m-Tolyl Methylamino 2-Keto meta-Ketamine m-Chlorophenyl Methylamino 2-Keto 7063-53-8 iso-Ketamine o-Chlorophenyl Methylamino 4-Keto 2-Fluorodeschloroketamine o-Fluorophenyl Methylamino 2-Keto 111982-50-4 3-Fluorodeschloroketamine m-Fluorophenyl Methylamino 2-Keto 2657761-23-2 Blixeprodil p-Fluorophenyl Methylamino 2-Keto 2881017-49-6 Bromoketamine o-Bromophenyl Methylamino 2-Keto 120807-70-7 TFMDCK o-Trifluoromethylphenyl Methylamino 2-Keto 1782149-73-8 TFMODCK o-Trifluoromethoxyphenyl Methylamino 2-Keto SN 35210 o-Chlorophenyl Carbomethoxybutylamino 2-Keto 1450615-41-4 Methoxetamine m-Methoxyphenyl Ethylamino 2-Keto 1239943-76-0 Methoxmetamine m-Methoxyphenyl Methylamino 2-Keto 1781829-56-8 Methoxpropamine m-Methoxyphenyl n-Propylamino 2-Keto 2504100-71-2 MXiPr m-Methoxyphenyl i-Propylamino 2-Keto Ethoxetamine (EXE) m-Ethoxyphenyl Ethylamino 2-Keto Deoxymethoxetamine (3-Me-2'-Oxo-PCE) m-Tolyl Ethylamino 2-Keto 2666932-45-0 MTXE m-Methylthio Ethylamino 2-Keto Br-MXE 2-bromo-5-methoxyphenyl Ethylamino 2-Keto Hydroxetamine (HXE) m-Hydroxyphenyl Ethylamino 2-Keto 1620054-73-0 HXM m-Hydroxyphenyl Methylamino 2-Keto 2F-NENDCK o-Fluorophenyl Ethylamino 2-Keto Fluorexetamine (FXE) m-Fluorophenyl Ethylamino 2-Keto 2-FXPr o-Fluorophenyl n-Propylamino 2-Keto 2-FXiPr o-Fluorophenyl i-Propylamino 2-Keto MXPCP m-Methoxyphenyl Piperidine 2-Keto Phencyclidine (PCP) Phenyl Piperidine - 77-10-1 PC3MP Phenyl 3-Methylpiperidine - 2201-41-4 PC4MP Phenyl 4-Methylpiperidine - 2201-42-5 PCTHP Phenyl 1,2,3,6-Tetrahydropyridine - Rolicyclidine (PCPy) Phenyl Pyrrolidine - 2201-39-0 PCDMPy Phenyl 3,3-Dimethylpyrrolidine - PCMo Phenyl Morpholine - 2201-40-3 Methoxy-PCM (2'-MeO-PCMo) o-Methoxyphenyl Morpholine - 1314323-88-0 3'-MeO-PCMo m-Methoxyphenyl Morpholine - 138873-80-0 4'-MeO-PCMo p-Methoxyphenyl Morpholine - Methyl-PCM (4'-Me-PCMo) p-Tolyl Morpholine - 120803-52-3 Hydroxy-methyl-PCM 2-Methyl-4-hydroxyphenyl Morpholine - 1314323-89-1 PYCP 2-Pyridinyl Piperidine - TCM 2-Thienyl Methylamino - 139401-07-3 TCE 2-Thienyl Ethylamino - 101589-62-2 TCPr 2-Thienyl Propylamino - Tenocyclidine (TCP) 2-Thienyl Piperidine - 21500-98-1 T3CP 3-Thienyl Piperidine - 19420-50-9 TCPy 2-Thienyl Pyrrolidine - 22912-13-6 TCTHPRice KC, et al. N-(1-thienylcycloalkyl)alkenylamines for treatment of neurotoxic injury. Patent US 5604255 2-Thienyl 1,2,3,6-Tetrahydropyridine - 111318-13-9 Tilmetamine 2-Thienyl Methylamino 2-Keto Tiletamine 2-Thienyl Ethylamino 2-Keto 14176-49-9 MXTE 4-Methoxy-2-thienyl Ethylamino 2-Keto Gacyclidine 2-Thienyl Piperidine 2-Methyl 68134-81-6 BDPC p-Bromophenyl Dimethylamino 4-Phenethyl-4-hydroxy 77239-98-6 C-8813 p-Bromophenyl Dimethylamino 4-(thiophen-2-yl)ethyl-4-hydroxy 616898-54-5 Dimetamine p-Tolyl Dimethylamino 4-Keto 65619-06-9 3''-OH-2'-Me-PCP o-Tolyl 3-Hydroxypiperidine - 4''-Ph-4''-OH-PCP Phenyl 4-Phenyl-4-hydroxypiperidine - 77179-39-6 BTCP Benzothiophen-2-yl Piperidine - 112726-66-6 BTCPy Benzothiophen-2-yl Pyrrolidine - GK-189Kamenka JM, et al. Substituted cyclic amines and pharmaceutical composition containing them. Patent US5248686, 28 September 1993 Naphthalen-2-yl Piperidine - 81490-58-6
Related compounds Other similar compounds exist where the base ring has been varied, or the amine chain replaced with other groups.Wallach JV. Structure activity relationship (SAR) studies of arylcycloalkylamines as N-methyl-D-aspartate receptor antagonists. PhD. Thesis, University of the Sciences in Philadelphia, 19 Dec 2014. More 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 one-tenth the potency, while the cycloheptyl and cyclooctyl derivatives are inactive, though some substituted arylcycloheptylamines retain activity. 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. Other compounds are known where the cyclohexyl base ring is replaced by rings such as norbornyl, adamantyl, tetralin, oxane, thiane Sisco E, Urbas A. Identification and Characterization of Designer Phencyclidines (PCPs) in Forensic Casework or piperidine.Gerhard O, Eberhard E. 4-amino-piperidines. US3311624A Conformationally constrained analogs have been prepared and researched by Morieti et al.
Structure Compound Aryl Substituent N Group Base ring CAS # Ketamir 2-Chlorophenyl Methylamine 2-Oxocyclopentyl PCPEP Phenyl Piperidine Cyclopentyl 23036-19-3 3F-PCHEPy 3-Fluorophenyl Pyrrolidine Cycloheptyl 3-MeO-PBCHP 3-Methoxyphenyl Piperidine Bicyclo[2.2.1]heptane PADP (P2AP) Phenyl Piperidine Adamantyl 72241-99-7 3-MeO-PTP 3-Methoxyphenyl Piperidine Tetralin HHFA Fused phenyl Amino Hexahydrofluorene DHPQ Phenyl Decahydroquinoline POXP Phenyl Piperidine Oxane PTHP Phenyl Piperidine Thiane