Chemistry:Arylcyclohexylamine

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Short description: Class of chemical compounds
Phencyclidine, the prototypical 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 (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 synthesis of phencyclidine 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

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

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

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

Structures Compound Aryl Substituent N Group Cyclohexyl ring CAS number
PCA structure.png PCA[24] Phenyl NH2 - 1934-71-0
PCM structure.png PCM[24] Phenyl Methylamino - 2201-16-3
Eticyclidine.svg Eticyclidine Phenyl Ethylamino - 2201-15-2
PCPr structure.png PCPr[25] Phenyl n-Propylamino - 18949-81-0
PCiP structure.png PCiP Phenyl Isopropylamino - 1195-42-2
PCAL structure.png PCAL [26] Phenyl Allylamino - 2185-95-7
PCBu structure.png PCBu Phenyl n-Butylamino - 73166-29-7
PCEOH structure.png PCEOH Phenyl Hydroxyethylamino - 2201-22-1
PCMEA structure.png PCMEA[27] Phenyl Methoxyethylamino - 2201-57-2
PCEEA structure.png PCEEA Phenyl Ethoxyethylamino - 1072895-05-6
PCMPA structure.png PCMPA Phenyl Methoxypropylamino - 2201-58-3
PCDM structure.png PCDM[24] Phenyl Dimethylamino - 2201-17-4
Dieticyclidine.svg Dieticyclidine Phenyl Diethylamino - 2201-19-6
2-HO-PCP structure.png 2-HO-PCP[6] Phenyl Piperidine 2-Hydroxy 94852-58-1
2-Me-PCP structure.png 2-Me-PCP[28] Phenyl Piperidine 2-Methyl 59397-29-4
2-MeO-PCP structure.png 2-MeO-PCP[29] Phenyl Piperidine 2-Methoxy 78636-34-7
O-PCP structure.png 2-Keto-PCP Phenyl Piperidine 2-Keto 101688-16-8
O-PCE structure.png Eticyclidone ("O-PCE") Phenyl Ethylamino 2-Keto 6740-82-5
O-PCPr structure.png 2-Keto-PCPr Phenyl n-Propylamino 2-Keto
4-Me-PCP structure.png 4-Methyl-PCP Phenyl Piperidine 4-Methyl 19420-52-1
4-Keto-PCP structure.png 4-Keto-PCP[30] Phenyl Piperidine 4-Keto 65620-13-5
2'-Cl-PCP structure.png 2'-Cl-PCP o-Chlorophenyl Piperidine - 2201-31-2
3'-Cl-PCP structure.png 3'-Cl-PCP m-Chlorophenyl Piperidine - 2201-32-3
2'-MeO-PCP structure.png 2'-MeO-PCP o-Methoxyphenyl Piperidine - 2201-34-5
3'-F-PCP structure.png 3'-F-PCP[31] m-Fluorophenyl Piperidine - 89156-99-0
3'-Me-PCP structure.png 3'-Me-PCP[32] m-Tolyl Piperidine - 2201-30-1
3'-Me-PCPy structure.png 3'-Me-PCPy m-Tolyl Pyrrolidine - 1622348-63-3
3'-NH2-PCP structure.png 3'-NH2-PCP m-Aminophenyl Piperidine - 72242-00-3
3-HO-PCP.png 3'-HO-PCP m-Hydroxyphenyl Piperidine - 79787-43-2
3-MeO-PCP structure.svg 3'-MeO-PCP m-Methoxyphenyl Piperidine - 72242-03-6
MDPCP structure.png 3',4'-MD-PCP 3,4-Methylenedioxyphenyl Piperidine -
3-MeO-PCE.svg 3'-MeO-PCE m-Methoxyphenyl Ethylamino - 1364933-80-1
3'-OH-PCE structure.png 3'-HO-PCE m-Hydroxyphenyl Ethylamino -
3'-MeO-PCPr structure.png 3'-MeO-PCPr m-Methoxyphenyl n-Propylamino - 1364933-81-2
3'-OH-PCPr structure.png 3'-HO-PCPr m-Hydroxyphenyl n-Propylamino -
MDPCPr structure.png 3',4'-MD-PCPr 3,4-Methylenedioxyphenyl n-Propylamino -
3'-MeO-PCPy structure.png 3'-MeO-PCPy[32] m-Methoxyphenyl Pyrrolidine - 1364933-79-8
4'-HO-PCP structure.png 4'-HO-PCP p-Hydroxyphenyl Piperidine - 66568-88-5
4-methoxyphencyclidine.png Methoxydine (4'-MeO-PCP) p-Methoxyphenyl Piperidine - 2201-35-6
4'-MeO-PCE structure.png 4'-MeO-PCE p-Methoxyphenyl Ethylamino -
4'-F-PCP structure.png 4'-F-PCP[31] p-Fluorophenyl Piperidine - 22904-99-0
4'-F-PCPy structure.png 4'-F-PCPy p-Fluorophenyl Pyrrolidine -
Arketamine structure.svg Arketamine o-Chlorophenyl Methylamino 2-Keto 33643-49-1
Deschloroketamine.png Deschloroketamine Phenyl Methylamino 2-Keto 7063-30-1
Esketamine2DCSD.svg Esketamine o-Chlorophenyl Methylamino 2-Keto 33643-46-8
Ketamine2DCSD.svg Ketamine o-Chlorophenyl Methylamino 2-Keto 6740-88-1
(2R,6R)-Hydroxynorketamine Formula V1.svg Hydroxynorketamine o-Chlorophenyl NH2 2-Keto, 6-Hydroxy 81395-70-2
N-Ethylnorketamine structure.png Ethketamine o-Chlorophenyl Ethylamino 2-Keto 1354634-10-8
NPNK structure.png NPNK o-Chlorophenyl n-Propylamino 2-Keto 2749326-65-4
Methoxyketamine.svg Methoxyketamine o-Methoxyphenyl Methylamino 2-Keto 7063-51-6
2-MeO-NEK structure.png 2-MeO-NEK[33] o-Methoxyphenyl Ethylamino 2-Keto
OMDCK structure.png oMDCK[34] o-Tolyl Methylamino 2-Keto 7063-37-8
MMDCK structure.png mMDCK m-Tolyl Methylamino 2-Keto
Meta-ketamine structure.png meta-Ketamine m-Chlorophenyl Methylamino 2-Keto 7063-53-8
Isoketamine structure.png iso-Ketamine o-Chlorophenyl Methylamino 4-Keto
2-Fluorodeschloroketamine.svg 2-Fluorodeschloroketamine o-Fluorophenyl Methylamino 2-Keto 111982-50-4
3FDCK structure.png 3-Fluorodeschloroketamine m-Fluorophenyl Methylamino 2-Keto 2657761-23-2
Bromoketamine structure.png Bromoketamine o-Bromophenyl Methylamino 2-Keto 120807-70-7
TFMDCK structure.png TFMDCK o-Trifluoromethylphenyl Methylamino 2-Keto 1782149-73-8
SN35210 structure.png SN 35210[35] o-Chlorophenyl Carbomethoxybutylamino 2-Keto 1450615-41-4
Methoxetamine2DCSD.svg Methoxetamine m-Methoxyphenyl Ethylamino 2-Keto 1239943-76-0
Methoxmetamine.png Methoxmetamine m-Methoxyphenyl Methylamino 2-Keto 1781829-56-8
MXPr structure.png Methoxpropamine m-Methoxyphenyl n-Propylamino 2-Keto 2504100-71-2
MXiPr structure.png MXiPr m-Methoxyphenyl i-Propylamino 2-Keto
Ethoxetamine structure.png Ethoxetamine m-Ethoxyphenyl Ethylamino 2-Keto
DMXE structure.svg Deoxymethoxetamine (3-Me-2'-Oxo-PCE) m-Tolyl Ethylamino 2-Keto 2666932-45-0
Br-MXE structure.png Br-MXE 2-bromo-5-methoxyphenyl Ethylamino 2-Keto
HXE structure.png Hydroxetamine (HXE) m-Hydroxyphenyl Ethylamino 2-Keto 1620054-73-0
HXM structure.png HXM m-Hydroxyphenyl Methylamino 2-Keto
FXE structure.png Fluorexetamine (FXE) m-Fluorophenyl Ethylamino 2-Keto
Phencyclidine structure.svg Phencyclidine (PCP) Phenyl Piperidine - 77-10-1
PC3MP structure.png PC3MP Phenyl 3-Methylpiperidine - 2201-41-4
PC4MP structure.png PC4MP Phenyl 4-Methylpiperidine - 2201-42-5
Rolicyclidine.svg Rolicyclidine (PCPy) Phenyl Pyrrolidine - 2201-39-0
PCDMPy structure.png PCDMPy Phenyl 3,3-Dimethylpyrrolidine -
PCMo structure.png PCMo Phenyl Morpholine - 2201-40-3
2'-MeO-PCMo structure.png Methoxy-PCM[7] (2'-MeO-PCMo) o-Methoxyphenyl Morpholine - 1314323-88-0
3-MeO-PCMo.svg 3'-MeO-PCMo m-Methoxyphenyl Morpholine - 138873-80-0
4'-MeO-PCMo structure.png 4'-MeO-PCMo p-Methoxyphenyl Morpholine -
4'-Me-PCMo structure.png Methyl-PCM[36] (4'-Me-PCMo) p-Tolyl Morpholine - 120803-52-3
2'-Me-4'-HO-PCMo structure.png Hydroxy-methyl-PCM 2-Methyl-4-hydroxyphenyl Morpholine - 1314323-89-1
PYCP structure.png PYCP [37] 2-Pyridinyl Piperidine -
TCM structure.png TCM 2-Thienyl Methylamino - 139401-07-3
TCE structure.png TCE 2-Thienyl Ethylamino - 101589-62-2
TCPr structure.png TCPr [38] 2-Thienyl Propylamino -
Tenocyclidine.svg Tenocyclidine (TCP) 2-Thienyl Piperidine - 21500-98-1
T3CP structure.png T3CP 3-Thienyl Piperidine - 19420-50-9
TCPy structure.png TCPy 2-Thienyl Pyrrolidine - 22912-13-6
Tiletamine.svg Tiletamine 2-Thienyl Ethylamino 2-Keto 14176-49-9
MXTE structure.png MXTE 4-Methoxy-2-thienyl Ethylamino 2-Keto
Gacyclidine.png Gacyclidine 2-Thienyl Piperidine 2-Methyl 68134-81-6
Bromadol Skeletal.png BDPC p-Bromophenyl Dimethylamino 4-Phenethyl-4-hydroxy 77239-98-6
C-8813.svg C-8813 p-Bromophenyl Dimethylamino 4-(thiophen-2-yl)ethyl-4-hydroxy 616898-54-5
Dimetamine structure.png Dimetamine[39] p-Tolyl Dimethylamino 4-Keto 65619-06-9
Ahmadi pcp 2010.svg 3''-OH-2'-Me-PCP [40] o-Tolyl 3-Hydroxypiperidine -
1-(1-PhCHX)-4-Ph-4-OH-piperidine structure.png 4''-Ph-4''-OH-PCP [41] Phenyl 4-Phenyl-4-hydroxypiperidine - 77179-39-6
BTCP.svg BTCP[42] Benzothiophen-2-yl Piperidine - 112726-66-6
BTCPy structure.png BTCPy[10] Benzothiophen-2-yl Pyrrolidine -
GK-189 structure.png GK-189[43] 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.[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 structure.png PCPEP Phenyl Piperidine Cyclopentyl 23036-19-3
3F-PCHEPy structure.png 3F-PCHEPy 3-Fluorophenyl Pyrrolidine Cycloheptyl
3-MeO-PBCHP structure.png 3-MeO-PBCHP 3-Methoxyphenyl Piperidine Bicyclo[2.2.1]heptane
PADP structure.png PADP (P2AP) Phenyl Piperidine Adamantyl 72241-99-7
Ahmadi 2010.svg 3-MeO-PTP 3-Methoxyphenyl Piperidine Tetralin
HHFA structure.png HHFA Fused phenyl Amino Hexahydrofluorene
DHPQ structure.png DHPQ Phenyl Decahydroquinoline
POXP structure.png POXP Phenyl Piperidine Oxane
PTHP structure.png PTHP Phenyl Piperidine Thiane
MPBPip structure.png MPBPip Phenyl Piperidine N-Methylpiperidine 36882-04-9
BnCP structure.png BnCP Benzyl Piperidine Cyclohexyl 22912-07-8
YNCP structure.png YNCP Ethynyl Piperidine Cyclohexyl 51165-02-7
ALCP structure.png ALCP Allyl Piperidine Cyclohexyl 7418-80-6
Piritramide2DACS.svg Piritramide Replaced by carboxamide Piperidine N-(3-cyano-3,3-diphenylpropyl)piperidine 302-41-0
PRE-084 SVG file.svg PRE-084 Phenyl Morpholinylethylcarboxylate Cyclohexyl 138847-85-5
Clofenciclan Structural Formulae.png Clofenciclan p-Chlorophenyl Diethylaminoethoxy Cyclohexyl 5632-52-0

References

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  43. ↑ Kamenka JM, et al. Substituted cyclic amines and pharmaceutical composition containing them. Patent US5248686, 28 September 1993
  44. ↑ 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.
  45. ↑ "Illicit synthesis of phencyclidine (PCP) and several of its analogs". Clinical Toxicology 9 (4): 553–60. 1976. doi:10.3109/15563657608988157. PMID 975751. 
  46. ↑ "Syntheses and N-methyl-D-aspartate receptor antagonist pharmacology of fluorinated arylcycloheptylamines". Medicinal Chemistry (Shariqah (United Arab Emirates)) 10 (8): 843–52. 2014. doi:10.2174/1573406410666140428104444. PMID 24773376. 
  47. ↑ "Structure-activity relationships of the cycloalkyl ring of phencyclidine". Journal of Medicinal Chemistry 24 (12): 1429–32. December 1981. doi:10.1021/jm00144a011. PMID 7310819. 
  48. ↑ "Geometries and conformational processes in phencyclidine and a rigid adamantyl analogue: variable-temperature NMR, X-ray crystallographic, and molecular mechanics studies". Journal of Medicinal Chemistry 26 (4): 479–86. April 1983. doi:10.1021/jm00358a005. PMID 6834381. 
  49. ↑ Sisco E, Urbas A. Identification and Characterization of Designer Phencyclidines (PCPs) in Forensic Casework
  50. ↑ Gerhard O, Eberhard E. 4-amino-piperidines. US3311624A
  51. ↑ "Rigid phencyclidine analogues. Binding to the phencyclidine and sigma 1 receptors". Journal of Medicinal Chemistry 41 (4): 468–77. February 1998. doi:10.1021/jm970059p. PMID 9484497. 

Further reading

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

External links



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