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Phencyclidine (PCP), the prototypal arylcyclohexylamine derivative

Arylcyclohexylamines, also known as arylcyclohexamines or arylcyclohexanamines, are a chemical class of psychotropic drugs and research chemicals. Many of the gem-substituted examples have either NMDA receptor antagonist and/or dopamine reuptake inhibitor (DRI) properties. Additionally, μ-opioid receptor agonism, α7 nicotinic receptor antagonism, and sigma receptor agonism are also reported for PCP-like agents in particular.

As a result of these effects, to varying degrees arylcyclohexylamines act as hallucinogenic dissociatives, anticonvulsants, anesthetics, analgesics, and stimulants. Thus, these are versatile agents with a wide range of possible pharmacological activities depending on the extent and range to which chemical modifications are implemented.

An arylcyclohexylamine is composed of a cyclohexylamine unit with an aryl moiety attachment. The aryl group is often 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, piperidino and pyrrolidino are examples of tertiary cycloalkylamines.

The various choice of substitutions that are made allows for "fine tuning" of the pharmacological profile that results.

Conformationally constrained PCP analog enantioselectively behaves as a potent NMDA receptor antagonist.[1]

In another study by a different cohort, rigid analogues of PCP were also made and tested.[2]

As example, whereas BTCP is a strong DRI (although effects on NMDA receptors are not as pronounced as for PCP),[3] phencyclidine is primarily an NMDA antagonist. Thus, radically different pharmacology was possible simply by changing the selection of the "aryl" moiety from a phenyl ring to a benzothiophene heterocycle.

The 3-hydroxy analog of PCP is also quite remarkable in that it is reported to be seven times more active than PCP itself as a blocker of the NMDA receptor.

Certain of these agents are also reported as being analgesics, particularly via their affinity for the mu-opiate receptors.[4] [5][6] The 4-phenyl-4-ol analog[7] of PCP is most probably related to groundbreaking work conducted on Bromadol.

4-hydroxy-3-methyl-4-phenyl-1-(1-phenylcyclohexyl)piperidine was also prepared and is reported to be an opioid agonist.[8]

"This folded three-dimensional relationship may be necessary for high-affinity interaction with the serotonin-uptake carrier and confers considerable structural homology between this portion of fluoxetine and the phenylcyclohexylamine substructure of sertraline and EXP-561."[9]

Note: Using the abbreviation "cyclohexamine" could actually cause confusion (see for cyclopentamine).

Chemical derivatives

1,1-Phenylcyclohexylamines
Compound N Substituent Other
Deschloroketamine HNMe 2-keto
Dieticyclidine -NEt2 -
Eticyclidine HNEt -
Phencyclamine -NH2 -
Phencyclidine Piperidine -
2-Methyl-PCP[10] Piperidine 2-methyl(cyclohexyl)
PCP-2-OH[11] Piperidine 2-hydroxy
PCP-2-OMe[12] Piperidine 2-methoxy
Rolicyclidine Pyrrolidino -
PCM HNMe -
PCPr[13] PrnNH -
PCEEA[14] HNC2H4OEt -
PCMEA[14] HNCH2OEt -
Bicyclic Phenylcyclohexylamines
Compound N Substituent Cyclohexane containing skeleton
EXP-561[15] NH2 bicyclo[2.2.2]octane
CP-24,441 NHMe 1,4-tetralin
fencamfamine NHEt norbornane
[1,1-Arylcyclohexylamines
Compound Aryl Substituent N Group Other
BDPC p-bromophenyl dimethylamine 4-phenethyl-4-hydroxy
3'-MeO-PCP m-Methoxyphenyl Piperidine -
4'-MeO-PCP p-Methoxyphenyl Piperidine -
Arketamine o-Chlorophenyl NHMe 2-keto(cyclohexyl)
BTCP Benzothiophen-2-yl Piperidine -
Esketamine o-Chlorophenyl NHMe 2-keto
Ethylketamine o-Chlorophenyl NHEt O
Gacyclidine 2-Thienyl Piperidine 2-Methyl(cyclohexyl)
Ketamine m-Chlorophenyl NHMe O
Tenocyclidine 2-Thienyl Piperidine -
Tiletamine 2-Thienyl NH-Ethyl O

In certain respects, epibatidine could be considered a type of conformationally restricted "aryl-cyclohexylamine".

References

  1. ^ Kozikowski, AP; Pang (1990). "Structural determinants of affinity for the phencyclidine binding site of the N-methyl-D-aspartate receptor complex: discovery of a rigid phencyclidine analogue of high binding affinity". Molecular pharmacology 37 (3): 352–7. PMID 2156150.   edit
  2. ^ Moriarty, R.; Enache, L.; Zhao, L.; Gilardi, R.; Mattson, M.; Prakash, O. (1998). "Rigid phencyclidine analogues. Binding to the phencyclidine and sigma 1 receptors". Journal of medicinal chemistry 41 (4): 468–477. doi:10.1021/jm970059p. PMID 9484497.   edit
  3. ^ 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.   edit
  4. ^ Itzhak, Y; Kalir; Weissman; Cohen (1981). "New analgesic drugs derived from phencyclidine". Journal of medicinal chemistry 24 (5): 496–9. doi:10.1021/jm00137a004. PMID 7241506.   edit
  5. ^ Itzhak, Y; Kalir; Weissman; Cohen (1981). "Receptor binding and antinociceptive properties of phencyclidine opiate-like derivatives". European journal of pharmacology 72 (4): 305–11. doi:10.1016/0014-2999(81)90568-9. PMID 6268418.   edit
  6. ^ Johnson, N; Itzhak; Pasternak (1984). "Interaction of two phencyclidine opiate-like derivatives with 3H-opioid binding sites". European journal of pharmacology 101 (3-4): 281–4. doi:10.1016/0014-2999(84)90171-7. PMID 6088255.   edit
  7. ^ Itzhak, Y; Simon (1984). "A novel phencyclidine analog interacts selectively with mu opioid receptors". The Journal of pharmacology and experimental therapeutics 230 (2): 383–6. PMID 6086884.   edit
  8. ^ Casy, AF; Dewar; Al-Deeb (1992). "Opioid properties of some isomeric derivatives of phencyclidine". The Journal of pharmacy and pharmacology 44 (1): 19–23. PMID 1350622.   edit
  9. ^ Robertson, DW; Jones; Swartzendruber; Yang; Wong (1988). "Molecular structure of fluoxetine hydrochloride, a highly selective serotonin-uptake inhibitor". Journal of medicinal chemistry 31 (1): 185–9. doi:10.1021/jm00396a030. PMID 3257267.   edit
  10. ^ Iorio, MA; Tomassini; Mattson; George; Jacobson (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): 2615–23. doi:10.1021/jm00112a041. PMID 1875352.   edit
  11. ^ 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): 528–32. PMID 16229117.   edit
  12. ^ Ahmadi, A; Mahmoudi (2006). "Synthesis with improved yield and study on the analgesic effect of 2-methoxyphencyclidine". Arzneimittel-Forschung 56 (5): 346–50. PMID 16821645.   edit
  13. ^ 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
  14. ^ a b 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
  15. ^ Maj, J; Skuza; Sowińska; Nowak (1987). "Pharmacological properties of EXP 561, a potential antidepressant drug". Journal of neural transmission 70 (1-2): 81–97. doi:10.1007/BF01252511. PMID 2822850.   edit

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