Arylcyclohexylamine

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{{cite web |title=4-(1-phenyl-cyclohexyl)-morpholine |url=https://www.chemsrc.com/cas/2201-40-3_1255636.html |website=CAS Number Search - chemsrc.com |publisher=chemsrc |access-date=15 March 2021}} see chart below for figure) in 1954, with PCMo described as a potent sedative.{{cite journal | vauthors = Morris H, Wallach J | title = From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs | journal = Drug Testing and Analysis | volume = 6 | issue = 7–8 | pages = 614–32 | year = 2014 | pmid = 24678061 | doi = 10.1002/dta.1620 }} 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.{{cite book | vauthors = Valter K, Arrizabalaga P | title = Designer Drugs Directory | publisher = Elsevier | date = 1998 | isbn = 0-444-20525-X}}{{cite book | vauthors = Wallach J, Brandt SD | chapter = Phencyclidine-Based New Psychoactive Substances | volume = 252| pages = 261–303| date = August 2018 | pmid = 30105474 | doi = 10.1007/164_2018_124| series = Handbook of Experimental Pharmacology | isbn = 978-3-030-10560-0 | title = New Psychoactive Substances }}{{cite book | vauthors = Wallach J, Brandt SD | title = New Psychoactive Substances | chapter = 1,2-Diarylethylamine- and Ketamine-Based New Psychoactive Substances | series = Handbook of Experimental Pharmacology | volume = 252 | pages = 305–352 | year = 2018 | pmid = 30196446 | doi = 10.1007/164_2018_148 | isbn = 978-3-030-10560-0 }}

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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.

Arylcyclohexylamines varyingly possess NMDA receptor antagonistic,{{cite journal | vauthors = Ahmadi A, Mahmoudi A | title = Synthesis and biological properties of 2-hydroxy-1-(1-phenyltetralyl)piperidine and some of its intermediates as derivatives of phencyclidine | journal = Arzneimittel-Forschung | volume = 55 | issue = 9 | pages = 528–32 | year = 2005 | pmid = 16229117 | doi = 10.1055/s-0031-1296900 | s2cid = 29006399 }}{{cite journal | vauthors = Ahmadi A, Khalili M, Hajikhani R, Naserbakht M | title = New morpholine analogues of phencyclidine: chemical synthesis and pain perception in rats | journal = Pharmacology, Biochemistry, and Behavior | volume = 98 | issue = 2 | pages = 227–33 | date = April 2011 | pmid = 21215770 | doi = 10.1016/j.pbb.2010.12.019 | s2cid = 24650035 }} dopamine reuptake inhibitory,{{cite journal | vauthors = Chaudieu I, Vignon J, Chicheportiche M, Kamenka JM, Trouiller G, Chicheportiche R | title = Role of the aromatic group in the inhibition of phencyclidine binding and dopamine uptake by PCP analogs | journal = Pharmacology, Biochemistry, and Behavior | volume = 32 | issue = 3 | pages = 699–705 | date = March 1989 | pmid = 2544905 | doi = 10.1016/0091-3057(89)90020-8 | s2cid = 7672918 }} and μ-opioid receptor agonistic{{cite journal | vauthors = Itzhak Y, Simon EJ | title = A novel phencyclidine analog interacts selectively with mu opioid receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 230 | issue = 2 | pages = 383–6 | date = August 1984 | doi = 10.1016/S0022-3565(25)21501-4 | pmid = 6086884 }} properties. Additionally, σ receptor agonistic,{{cite journal | vauthors = He XS, Raymon LP, Mattson MV, Eldefrawi ME, de Costa BR | title = Synthesis and biological evaluation of 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine homologues at dopamine-uptake and phencyclidine- and sigma-binding sites | journal = Journal of Medicinal Chemistry | volume = 36 | issue = 9 | pages = 1188–93 | date = April 1993 | pmid = 8098066 | doi = 10.1021/jm00061a009 }} nACh receptor antagonistic,{{cite journal | vauthors = Eterović VA, Lu R, Eakin AE, Rodríguez AD, Ferchmin PA | title = Determinants of phencyclidine potency on the nicotinic acetylcholine receptors from muscle and electric organ | journal = Cellular and Molecular Neurobiology | volume = 19 | issue = 6 | pages = 745–57 | date = December 1999 | pmid = 10456235 | doi = 10.1023/A:1006905106834 | s2cid = 22266452 | doi-access = free | pmc = 11545680 }} and D₂ receptor agonistic{{cite journal | vauthors = Seeman P, Ko F, Tallerico T | title = Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics | journal = Molecular Psychiatry | volume = 10 | issue = 9 | pages = 877–83 | date = September 2005 | pmid = 15852061 | doi = 10.1038/sj.mp.4001682 | doi-access = }} 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.{{cite journal | vauthors = al-Deeb OA | title = New analgesics derived from the phencyclidine analogue thienylcyclidine | journal = Arzneimittel-Forschung | volume = 46 | issue = 5 | pages = 505–8 | date = May 1996 | pmid = 8737636 }}{{cite journal | vauthors = Ahmadi A, Khalili M, Hajikhani R, Hosseini H, Afshin N, Nahri-Niknafs B | title = Synthesis and study the analgesic effects of new analogues of ketamine on female wistar rats | journal = Medicinal Chemistry | volume = 8 | issue = 2 | pages = 246–51 | date = March 2012 | pmid = 22385170 | doi = 10.2174/157340612800493683 | s2cid = 42842315 }}{{cite journal | vauthors = Ahmadi A, Khalili M, Abbassi S, Javadi M, Mahmoudi A, Hajikhani R | title = Synthesis and study on analgesic effects of 1-[1-(4-methylphenyl) (cyclohexyl)] 4-piperidinol and 1-[1-(4-methoxyphenyl) (cyclohexyl)] 4-piperidinol as two new phencyclidine derivatives | journal = Arzneimittel-Forschung | volume = 59 | issue = 4 | pages = 202–6 | year = 2009 | pmid = 19517897 | doi = 10.1055/s-0031-1296386 | s2cid = 5402425 }}{{cite journal | vauthors = Ahmadi A, Khalili M, Marami S, Ghadiri A, Nahri-Niknafs B | title = Synthesis and pain perception of new analogues of phencyclidine in NMRI male mice | journal = Mini Reviews in Medicinal Chemistry | volume = 14 | issue = 1 | pages = 64–71 | date = January 2014 | pmid = 24251803 | doi = 10.2174/1389557513666131119203551 }}{{cite journal | vauthors = Ahmadi A, Solati J, Hajikhani R, Pakzad S | title = Synthesis and analgesic effects of new pyrrole derivatives of phencyclidine in mice | journal = Arzneimittel-Forschung | volume = 61 | issue = 5 | pages = 296–300 | year = 2011 | pmid = 21755813 | doi = 10.1055/s-0031-1296202 | s2cid = 24287727 }}{{cite journal | vauthors = Ahmadi A, Khalili M, Hajikhani R, Barghi L, Mihandoust F | title = Synthesis and determination of chronic and acute thermal and chemical pain activities of a new derivative of phencyclidine in rats | journal = Iranian Journal of Pharmaceutical Research | volume = 9 | issue = 4 | pages = 379–85 | year = 2010 | pmid = 24381602 | pmc = 3870061 }}{{cite journal | vauthors = Ahmadi A, Khalili M, Mihandoust F, Barghi L | title = Synthesis and determination of acute and chronic pain activities of 1-[1-(3-methylphenyl) (tetralyl)]piperidine as a new derivative of phencyclidine via tail immersion and formalin tests | journal = Arzneimittel-Forschung | volume = 60 | issue = 1 | pages = 30–5 | year = 2010 | pmid = 20184224 | doi = 10.1055/s-0031-1296245 | s2cid = 23966936 }}{{cite journal | vauthors = Hajikhani R, Ahmadi A, Naderi N, Yaghoobi K, Shirazizand Z, Rezaee NM, Niknafs BN | title = Effect of phencyclidine derivatives on anxiety-like behavior using an elevated-plus maze test in mice | journal = Advances in Clinical and Experimental Medicine | volume = 21 | issue = 3 | pages = 307–12 | year = 2012 | pmid = 23214193 }}{{cite journal | vauthors = Ahmadi A, Khalili M, Mirza B, Mohammadi-Diz M, Azami-Lorestani F, Ghaderi P, Nahri-Niknafs B | title = Synthesis and Antinociception Activities of Some Novel Derivatives of Phencyclidine with Substituted Aminobenzothiazoles | journal = Mini Reviews in Medicinal Chemistry | volume = 17 | issue = 1 | pages = 78–84 | year = 2017 | pmid = 27121715 | doi = 10.2174/1389557516666160428112532 }}{{excessive citations inline|date=April 2025}} 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,{{cite journal | vauthors = Lednicer D, VonVoigtlander PF | title = 4-(p-Bromophenyl)-4-(dimethylamino)-1-phenethylcyclohexanol, an extremely potent respresentative of a new analgesic series | journal = Journal of Medicinal Chemistry | volume = 22 | issue = 10 | pages = 1157–8 | date = October 1979 | pmid = 513062 | doi = 10.1021/jm00196a001 }} while PRE-084 is a selective sigma receptor agonist.{{cite journal | vauthors = Maurice T, Su TP, Parish DW, Nabeshima T, Privat A | title = PRE-084, a sigma selective PCP derivative, attenuates MK-801-induced impairment of learning in mice | journal = Pharmacology, Biochemistry, and Behavior | volume = 49 | issue = 4 | pages = 859–69 | date = December 1994 | pmid = 7886099 | doi = 10.1016/0091-3057(94)90235-6 | s2cid = 54306053 | url = https://zenodo.org/record/1258299 }} Thus, radically different pharmacology is possible through different structural combinations.

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.

Image:4methylPCPisomer_structure.png

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.

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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,{{cite journal | vauthors = Shulgin AT, Mac Lean DE | title = Illicit synthesis of phencyclidine (PCP) and several of its analogs | journal = Clinical Toxicology | volume = 9 | issue = 4 | pages = 553–60 | date = 1976 | pmid = 975751 | doi = 10.3109/15563657608988157 }} while the cycloheptyl and cyclooctyl derivatives are inactive, though some substituted arylcycloheptylamines retain activity.{{cite journal | vauthors = Sun S, Wallach J, Adejare A | title = Syntheses and N-methyl-D-aspartate receptor antagonist pharmacology of fluorinated arylcycloheptylamines | journal = Medicinal Chemistry | location = Shariqah (United Arab Emirates) | volume = 10 | issue = 8 | pages = 843–52 | date = 2014 | pmid = 24773376 | doi = 10.2174/1573406410666140428104444 }} 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.{{cite journal | vauthors = McQuinn RL, Cone EJ, Shannon HE, Su TP | title = Structure-activity relationships of the cycloalkyl ring of phencyclidine | journal = Journal of Medicinal Chemistry | volume = 24 | issue = 12 | pages = 1429–32 | date = December 1981 | pmid = 7310819 | doi = 10.1021/jm00144a011 }} Other compounds are known where the cyclohexyl base ring is replaced by rings such as norbornyl, adamantyl,{{cite journal | vauthors = Eaton TA, Houk KN, Watkins SF, Fronczek FR | title = Geometries and conformational processes in phencyclidine and a rigid adamantyl analogue: variable-temperature NMR, X-ray crystallographic, and molecular mechanics studies | journal = Journal of Medicinal Chemistry | volume = 26 | issue = 4 | pages = 479–86 | date = April 1983 | pmid = 6834381 | doi = 10.1021/jm00358a005 }} tetralin, oxane, thiane [https://chemrxiv.org/engage/api-gateway/chemrxiv/assets/orp/resource/item/62c743ca638326c3ed445d91/original/identification-and-characterization-of-designer-phencyclidines-pc-ps-in-forensic-casework.pdf Sisco E, Urbas A. Identification and Characterization of Designer Phencyclidines (PCPs) in Forensic Casework] or piperidine.[https://patents.google.com/patent/US3311624A Gerhard O, Eberhard E. 4-amino-piperidines. US3311624A] Conformationally constrained analogs have been prepared and researched by Morieti et al.{{cite journal | vauthors = Moriarty RM, Enache LA, Zhao L, Gilardi R, Mattson MV, Prakash O | title = Rigid phencyclidine analogues. Binding to the phencyclidine and sigma 1 receptors | journal = Journal of Medicinal Chemistry | volume = 41 | issue = 4 | pages = 468–77 | date = February 1998 | pmid = 9484497 | doi = 10.1021/jm970059p }}

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{{Reflist}}

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• {{cite journal | vauthors = Morris H, Wallach J | title = From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs | journal = Drug Testing and Analysis | volume = 6 | issue = 7–8 | pages = 614–32 | year = 2014 | pmid = 24678061 | doi = 10.1002/dta.1620 }}

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• [http://www.erowid.org/archive/rhodium/chemistry/pcp/ Synthesis and Effects of PCP Analogs]
• [https://www.vice.com/read/interview-with-ketamine-chemist-704-v18n2 Interview with a Ketamine Chemist]
• [https://nervewing.blogspot.com/2020/10/new-drugs-designing-novel.html?m=1 New Drugs: Designing Novel Arylcyclohexylamines]

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