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.

Contents

History [edit]

The arylcyclohexylamines were originally developed as anesthetics in the 1960s with ketamine and phencyclidine (PCP) being the first members of the class to be synthesized.[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.

Chemistry [edit]

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.

General structure of arylcyclohexylamines

Pharmacology [edit]

Arylcyclohexylamines varyingly possess NMDA receptor antagonistic,[2][3] dopamine reuptake inhibitory,[4] and μ-opioid receptor agonistic[5] properties. Additionally, σ receptor agonistic,[6] nACh receptor antagonistic,[7] and D2 receptor agonistic[8] 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 psychomimetic effects.[8]

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,[4] PCP is primarily an NMDA antagonist,[2] and BDPC is a superpotent μ-opioid agonist,[9] while PRE-084 is a selective sigma receptor agonist.[10] Thus, radically different pharmacology is possible through different structural combinations.

List of arylcyclohexylamines [edit]

Compound Aryl Substituent N Group Cyclohexyl ring
PCA Phenyl NH2 -
PCM Phenyl Methylamino -
Eticyclidine Phenyl Ethylamino -
PCPr[11] Phenyl n-Propylamino -
PCiP Phenyl Isopropylamino -
PCBu Phenyl n-Butylamino -
PCEOH Phenyl Hydroxyethylamino -
PCMEA[12] Phenyl Methoxyethylamino -
PCEEA Phenyl Ethoxyethylamino -
PCMPA Phenyl Methoxypropylamino -
PCDM Phenyl Dimethylamino -
Dieticyclidine Phenyl Diethylamino -
2-HO-PCP[13] Phenyl Piperidine 2-Hydroxy
2-Me-PCP[14] Phenyl Piperidine 2-Methyl
2-MeO-PCP[15] Phenyl Piperidine 2-Methoxy
2-Keto-PCP Phenyl Piperidine 2-Keto
2-Keto-PCE Phenyl Ethylamino 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 m-Fluorophenyl Piperidine -
3'-Me-PCP m-Methylphenyl Piperidine -
3'-NH2-PCP m-Aminophenyl Piperidine -
3'-HO-PCP m-Hydroxyphenyl Piperidine -
3-MeO-PCP m-Methoxyphenyl Piperidine -
3'-MeO-PCE m-Methoxyphenyl Ethylamino -
3'-MeO-PCPr m-Methoxyphenyl n-Propylamino -
3'-MeO-PCPy m-Methoxyphenyl Pyrrolidine -
4'-OH-PCP p-Hydroxyphenyl Piperidine -
Methoxydine (4-MeO-PCP) p-Methoxyphenyl Piperidine -
4'-F-PCP p-Fluorophenyl Piperidine -
Arketamine o-Chlorophenyl Methylamino 2-Keto
Deschloroketamine Phenyl Methylamino 2-Keto
Esketamine o-Chlorophenyl Methylamino 2-Keto
Ethketamine o-Chlorophenyl Ethylamino 2-Keto
Ketamine o-Chlorophenyl Methylamino 2-Keto
Methoxyketamine o-Methoxyphenyl Methylamino 2-Keto
Fluoroketamine o-Fluorophenyl Methylamino 2-Keto
Bromoketamine o-Bromophenyl Methylamino 2-Keto
Methoxetamine m-Methoxyphenyl 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[3] o-Methoxyphenyl Morpholine -
Methyl-PCM[16] p-Methylphenyl Morpholine -
Hydroxy-methyl-PCM 2-Methyl-4-hydroxyphenyl Morpholine -
TCM 2-Thienyl Methylamino -
TCE 2-Thienyl Ethylamino -
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
Dimetamine p-Methylphenyl Dimethylamino 4-Keto
BTCP[17] Benzothiophen-2-yl Piperidine -
PRE-084 Phenyl Morpholinylethylcarboxylate -

References [edit]

  1. ^ Domino, EF (2010 Sep). "Taming the ketamine tiger. 1965.". Anesthesiology 113 (3): 678–84. doi:10.1097/ALN.0b013e3181ed09a2. PMID 20693870. 
  2. ^ a b Ahmadi, A.; Mahmoudi (2005). "Synthesis and biological properties of 2-hydroxy-1-(1-phenyltetralyl)piperidine and some of its intermediates as derivatives of phencyclidine". Arzneimittel-Forschung 55 (9): 528–532. PMID 16229117.  More than one of |author2= and |last2= specified (help) edit
  3. ^ a b Ahmadi, A.; Khalili, M.; Hajikhani, R.; Naserbakht, M. (2011). "New morpholine analogues of phencyclidine: Chemical synthesis and pain perception in rats". Pharmacology Biochemistry and Behavior 98 (2): 227–233. doi:10.1016/j.pbb.2010.12.019. PMID 21215770.  edit
  4. ^ a b Chaudieu, I.; Vignon; Chicheportiche; Kamenka; Trouiller; Chicheportiche (1989). "Role of the aromatic group in the inhibition of phencyclidine binding and dopamine uptake by PCP analogs". Pharmacology, Biochemistry, and Behavior 32 (3): 699–705. doi:10.1016/0091-3057(89)90020-8. PMID 2544905.  More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help); More than one of |author5= and |last5= specified (help); More than one of |author6= and |last6= specified (help) edit
  5. ^ Itzhak, Y.; Simon (1984). "A novel phencyclidine analog interacts selectively with mu opioid receptors". The Journal of Pharmacology and Experimental Therapeutics 230 (2): 383–386. PMID 6086884.  More than one of |author2= and |last2= specified (help) edit
  6. ^ He, X. S.; Raymon, L. P.; Mattson, M. V.; Eldefrawi, M. E.; De Costa, B. R. (1993). "Synthesis and biological evaluation of 1-1-(2-benzobthienyl)cyclohexylpiperidine homologues at dopamine-uptake and phencyclidine- and sigma-binding sites". Journal of Medical Chemistry 36 (9): 1188–1193. PMID 8098066.  edit
  7. ^ Eterović, V. A.; Lu, R.; Eakin, A. E.; Rodríguez, A. D.; Ferchmin, P. A. (1999). "Determinants of phencyclidine potency on the nicotinic acetylcholine receptors from muscle and electric organ". Cellular and molecular neurobiology 19 (6): 745–757. PMID 10456235.  edit
  8. ^ a b Seeman, P.; Ko, F.; Tallerico, T. (2005). "Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics". Molecular Psychiatry 10 (9): 877–883. doi:10.1038/sj.mp.4001682. PMID 15852061.  edit
  9. ^ Lednicer, D.; Vonvoigtlander, P. F. (1979). "4-(p-Bromophenyl)-4-(dimethylamino)-1-phenethylcyclohexanol, an extremely potent representative of a new analgesic series". Journal of Medicinal Chemistry 22 (10): 1157–1158. doi:10.1021/jm00196a001. PMID 513062.  edit
  10. ^ Maurice, T.; Su, T. P.; Parish, D. W.; Nabeshima, T.; Privat, A. (1994). "PRE-084, a sigma selective PCP derivative, attenuates MK-801-induced impairment of learning in mice". Pharmacology, Biochemistry, and Behavior 49 (4): 859–869. doi:10.1016/0091-3057(94)90235-6. PMID 7886099.  edit
  11. ^ Sauer, C.; Peters, F.; Staack, R.; Fritschi, G.; Maurer, H. (2008). "Metabolism and toxicological detection of a new designer drug, N-(1-phenylcyclohexyl)propanamine, in rat urine using gas chromatography-mass spectrometry". Journal of Chromatography A 1186 (1–2): 380–390. doi:10.1016/j.chroma.2007.11.002. PMID 18035363.  edit
  12. ^ Sauer, C.; Peters, F.; Schwaninger, A.; Meyer, M.; Maurer, H. (2009). "Investigations on the cytochrome P450 (CYP) isoenzymes involved in the metabolism of the designer drugs N-(1-phenyl cyclohexyl)-2-ethoxyethanamine and N-(1-phenylcyclohexyl)-2-methoxyethanamine". Biochemical pharmacology 77 (3): 444–450. doi:10.1016/j.bcp.2008.10.024. PMID 19022226.  edit
  13. ^ Ahmadi, A.; Mahmoudi (2005). "Synthesis and biological properties of 2-hydroxy-1-(1-phenyltetralyl)piperidine and some of its intermediates as derivatives of phencyclidine". Arzneimittel-Forschung 55 (9): 528–532. PMID 16229117.  More than one of |author2= and |last2= specified (help) edit
  14. ^ Iorio, M. A.; Tomassini, L.; Mattson, M. V.; George, C.; Jacobson, A. E. (1991). "Synthesis, stereochemistry, and biological activity of the 1-(1-phenyl-2-methylcyclohexyl)piperidines and the 1-(1-phenyl-4-methylcyclohexyl)piperidines. Absolute configuration of the potent trans-(-)-1-(1-phenyl-2-methylcyclohexyl)piperidine". Journal of Medicinal Chemistry 34 (8): 2615–2623. doi:10.1021/jm00112a041. PMID 1875352.  edit
  15. ^ Ahmadi, A.; Mahmoudi, A. (2006). "Synthesis with improved yield and study on the analgesic effect of 2-methoxyphencyclidine". Arzneimittel-Forschung 56 (5): 346–350. PMID 16821645.  edit
  16. ^ Ahmadi A, Khalili M, Hajikhani R, Naserbakht M (2011). "Synthesis and determination of acute and chronic pain activities of 1-[1-(4-methylphenyl) (cyclohexyl)] morpholine as a new phencyclidine derivative in rats". Arzneimittel-Forschung 61 (2): 92–7. PMID 21428243. 
  17. ^ Vignon, J.; Pinet, V.; Cerruti, C.; Kamenka, J. M.; Chicheportiche, R. (1988). "3HN-1-(2-benzo(b)thiophenyl)cyclohexylpiperidine (3HBTCP): A new phencyclidine analog selective for the dopamine uptake complex". European Journal of Pharmacology 148 (3): 427–436. doi:10.1016/0014-2999(88)90122-7. PMID 3384005.  edit

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