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Arylcyclohexylamine

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

Phencyclidine, the prototypical arylcyclohexylamine derivative.

History

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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 pharmaceutical industry until the 1950s. PCE was reported in 1953 and PCMo (4-(1-phenyl-cyclohexyl)-morpholine[1] see chart below for figure) in 1954, with PCMo described as a potent sedative.[2] Arylcyclohexylamine anesthetics were intensively investigated at Parke-Davis, beginning with the 1956 studies of PCP and later the related compound ketamine.[2] 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.[3][4][5]

Structure

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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 methylamine or ethylamine, or tertiary cycloalkylamines such as piperidine and pyrrolidine, are the most commonly encountered N-substituents.

Pharmacology

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Arylcyclohexylamines varyingly possess NMDA receptor antagonistic,[6][7] dopamine reuptake inhibitory,[8] and μ-opioid receptor agonistic[9] properties. Additionally, σ receptor agonistic,[10] nACh receptor antagonistic,[11] and D2 receptor agonistic[12] 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.[12]

These are versatile agents with a wide range of possible pharmacological activities depending on the extent and range to which chemical modifications are implemented.[13][14][15][16][17][18][19][20][21] 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,[8] PCP is primarily an NMDA antagonist,[6] and BDPC is a potent μ-opioid agonist,[22] while PRE-084 is a selective sigma receptor agonist.[23] Thus, radically different pharmacology is possible through different structural combinations.

Notes on numbering

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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.

 
4-Methyl-PCP, 4'-Methyl-PCP and 4''-Methyl-PCP (left to right)

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

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Structures Compound Aryl Substituent N Group Cyclohexyl ring CAS number
  PCA[24] Phenyl NH2 - 1934-71-0
  PCM[24] Phenyl Methylamino - 2201-16-3
  Eticyclidine Phenyl Ethylamino - 2201-15-2
  PCPr[25] Phenyl n-Propylamino - 18949-81-0
  PCiP Phenyl Isopropylamino - 1195-42-2
  PCAL [26] Phenyl Allylamino - 2185-95-7
  PCBu Phenyl n-Butylamino - 73166-29-7
  PCEOH Phenyl Hydroxyethylamino - 2201-22-1
  PCMEA[27] Phenyl Methoxyethylamino - 2201-57-2
  PCEEA Phenyl Ethoxyethylamino - 1072895-05-6
  PCMPA Phenyl Methoxypropylamino - 2201-58-3
  PCDM[24] Phenyl Dimethylamino - 2201-17-4
  Dieticyclidine Phenyl Diethylamino - 2201-19-6
  2-HO-PCP[6] Phenyl Piperidine 2-Hydroxy 94852-58-1
  2-Me-PCP[28] Phenyl Piperidine 2-Methyl 59397-29-4
  2-MeO-PCP[29] Phenyl Piperidine 2-Methoxy 78636-34-7
  2-Keto-PCP Phenyl Piperidine 2-Keto 101688-16-8
  Eticyclidone ("O-PCE") Phenyl Ethylamino 2-Keto 6740-82-5
  2-Keto-PCPr Phenyl n-Propylamino 2-Keto
  4-Methyl-PCP Phenyl Piperidine 4-Methyl 19420-52-1
  4-Keto-PCP[30] Phenyl Piperidine 4-Keto 65620-13-5
  2'-Cl-PCP o-Chlorophenyl Piperidine - 2201-31-2
  3'-Cl-PCP m-Chlorophenyl Piperidine - 2201-32-3
  2'-MeO-PCP o-Methoxyphenyl Piperidine - 2201-34-5
  3'-F-PCP[31] m-Fluorophenyl Piperidine - 89156-99-0
  3'-Me-PCP[32] 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',4'-MD-PCP 3,4-Methylenedioxyphenyl Piperidine -
  3'-MeO-PCE m-Methoxyphenyl Ethylamino - 1364933-80-1
  3'-HO-PCE m-Hydroxyphenyl 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[32] m-Methoxyphenyl Pyrrolidine - 1364933-79-8
  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[31] 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
  Methoxyketamine o-Methoxyphenyl Methylamino 2-Keto 7063-51-6
  2-MeO-NEK[33] o-Methoxyphenyl Ethylamino 2-Keto
  oMDCK[34] 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
  Bromoketamine o-Bromophenyl Methylamino 2-Keto 120807-70-7
  TFMDCK o-Trifluoromethylphenyl Methylamino 2-Keto 1782149-73-8
  SN 35210[35] 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 m-Ethoxyphenyl Ethylamino 2-Keto
  Deoxymethoxetamine (3-Me-2'-Oxo-PCE) m-Tolyl Ethylamino 2-Keto 2666932-45-0
  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
  Phencyclidine (PCP) Phenyl Piperidine - 77-10-1
  PC3MP Phenyl 3-Methylpiperidine - 2201-41-4
  PC4MP Phenyl 4-Methylpiperidine - 2201-42-5
  Rolicyclidine (PCPy) Phenyl Pyrrolidine - 2201-39-0
  PCDMPy Phenyl 3,3-Dimethylpyrrolidine -
  PCMo Phenyl Morpholine - 2201-40-3
  Methoxy-PCM[7] (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[36] (4'-Me-PCMo) p-Tolyl Morpholine - 120803-52-3
  Hydroxy-methyl-PCM 2-Methyl-4-hydroxyphenyl Morpholine - 1314323-89-1
  PYCP [37] 2-Pyridinyl Piperidine -
  TCM 2-Thienyl Methylamino - 139401-07-3
  TCE 2-Thienyl Ethylamino - 101589-62-2
  TCPr [38] 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
  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[39] p-Tolyl Dimethylamino 4-Keto 65619-06-9
  3''-OH-2'-Me-PCP [40] o-Tolyl 3-Hydroxypiperidine -
  4''-Ph-4''-OH-PCP [41] Phenyl 4-Phenyl-4-hydroxypiperidine - 77179-39-6
  BTCP[42] Benzothiophen-2-yl Piperidine - 112726-66-6
  BTCPy[10] Benzothiophen-2-yl Pyrrolidine -
  GK-189[43] Naphthalen-2-yl Piperidine - 81490-58-6
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Other similar compounds exist where the base ring has been varied, or the amine chain replaced with other groups.[44] 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,[45] while the cycloheptyl and cyclooctyl derivatives are inactive, though some substituted arylcycloheptylamines retain activity.[46] 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.[47] Other compounds are known where the cyclohexyl base ring is replaced by rings such as norbornyl, adamantyl,[48] tetralin, oxane, thiane [49] or piperidine.[50] Conformationally constrained analogs have been prepared and researched by Morieti et al.[51]

Structure Compound Aryl Substituent N Group Base ring CAS number
  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
  MPBPip Phenyl Piperidine N-Methylpiperidine 36882-04-9
  BnCP Benzyl Piperidine Cyclohexyl 22912-07-8
  YNCP Ethynyl Piperidine Cyclohexyl 51165-02-7
  ALCP Allyl Piperidine Cyclohexyl 7418-80-6
  Piritramide Replaced by carboxamide Piperidine N-(3-cyano-3,3-diphenylpropyl)piperidine 302-41-0
  PRE-084 Phenyl Morpholinylethylcarboxylate Cyclohexyl 138847-85-5
  Clofenciclan p-Chlorophenyl Diethylaminoethoxy Cyclohexyl 5632-52-0

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Further reading

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  • Morris H, Wallach J (2014). "From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs". Drug Testing and Analysis. 6 (7–8): 614–32. doi:10.1002/dta.1620. PMID 24678061.
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