Arylcyclohexylamines
Arylcyclohexylamines , also known as arylcyclohexamines or arylcyclohexanamines , are a chemical class of (experimental) medicinal products and designer drugs .
history
Phencyclidine (PCP) is believed to be the first arylcyclohexylamine discovered with recognized anesthetic properties. In the scientific literature, however, several arylcyclohexylamines have been described before PCP, starting with PCA (1-phenylcyclohexan-1-amine), the synthesis of which was first published in 1907. Eticyclidine (PCE) was discovered in 1953 and PCMo in 1954, the latter compound having been described as a potent sedative . Arylcyclohexylamine anesthetics were extensively studied by Parke-Davis , beginning with the synthesis of PCP and later the related compound ketamine in 1956. In the 1970s, these compounds, especially PCP and its analogues , were considered to be due to their dissociative , hallucinogenic and euphoric effects used illegal drugs . Since then, the group of substances has been expanded by scientific research on stimulants , analgesics and neuroprotectants, as well as by chemists looking for novel recreational drugs.
structure
An arylcyclohexylamine consists of a cyclohexylamine which is substituted with an aryl group geminally to the amino group . In the simplest cases, the aryl unit is a phenyl ring , optionally with additional substituents.
The amino group is usually not primary ; the most common N -substituents in the secondary amines are the methyl or ethyl group and the tertiary amines are mostly piperidine and pyrrolidine derivatives .
Pharmacology and pharmacodynamics
Arylcyclohexylamines have different NMDA receptor - antagonistic , dopamine reuptake inhibiting , and μ-opioid receptor - agonistic properties. In addition, they have an agonistic effect on the sigma receptor , antagonistic on nicotine receptors and agonistic on dopamine D 2 receptors . Different pharmacological effects were observed depending on the active ingredients . The antagonism of the NMDA receptor confers anesthetic , antispasmodic , neuroprotective and dissociative effects; the blockade of the dopamine transporter mediates stimulating and euphoric effects as well as psychoses in high doses; and activation of the μ-opioid receptor causes analgesic and euphoric effects. The stimulation of the σ and D2 receptors can also contribute to hallucinogenic and psychotomimetic effects.
Arylcyclohexylamines are versatile active ingredients with a broad spectrum of possible pharmacological effects , depending on the scope and area in which structural chemical modifications have been carried out. The various possibilities of modification of the chemical structure allow a "fine tuning" of the resulting pharmacological and pharmacodynamic profile. z. B. Benocyclidine (BTCP) is a selective dopamine reuptake inhibitor , PCP is primarily an NMDA antagonist, and bromadol (BDPC) is a potent μ-opioid agonist, while PRE-084 is a selective sigma receptor agonist . Thus, radically different pharmacology and pharmacodynamics are possible through different structural combinations.
List of arylcyclohexylamines
structure | connection | Aryl group | Amine group | Cyclohexyl ring |
---|---|---|---|---|
PCA | Phenyl | NH 2 | - | |
PCM | Phenyl | Methylamine | - | |
Eticyclidine | Phenyl | Ethylamine | - | |
PCPr | Phenyl | n -propylamine | - | |
PCiP | Phenyl | Isopropylamine | - | |
PCAL | Phenyl | Allylamine | - | |
PCBu | Phenyl | n -butylamine | - | |
PCEOH | Phenyl | Hydroxyethylamine | - | |
PCMEA | Phenyl | Methoxyethylamine | - | |
PCEEA | Phenyl | Ethoxyethylamine | - | |
PCMPA | Phenyl | Methoxypropylamine | - | |
PCDM | Phenyl | Dimethylamine | - | |
Dieticyclidine | Phenyl | Diethylamine | - | |
2-HO-PCP | Phenyl | Piperidine | 2-hydroxy | |
2-Me-PCP | Phenyl | Piperidine | 2-methyl | |
2-MeO-PCP | Phenyl | Piperidine | 2-methoxy | |
2-keto-PCP | Phenyl | Piperidine | 2-oxo | |
Eticyclidone ("O-PCE") | Phenyl | Ethylamine | 2-oxo | |
2-keto-PCPr | Phenyl | n -propylamine | 2-oxo | |
4-methyl-PCP | Phenyl | Piperidine | 4-methyl | |
4-keto-PCP | Phenyl | Piperidine | 4-oxo | |
2'-Cl-PCP | o -chlorophenyl | Piperidine | - | |
2'-MeO-PCP | o -methoxyphenyl | Piperidine | - | |
3'-F-PCP | m -fluorophenyl | Piperidine | - | |
3'-Me-PCP | m -Tolyl | Piperidine | - | |
3'-Me-PCPy | m -Tolyl | Pyrrolidine | - | |
3'-NH 2 -PCP | m -aminophenyl | Piperidine | - | |
3'-HO-PCP | m -hydroxyphenyl | Piperidine | - | |
3'-MeO-PCP | m -methoxyphenyl | Piperidine | - | |
3 ', 4'-MD-PCP | 3,4-methylenedioxyphenyl | Piperidine | - | |
3'-MeO-PCE | m -methoxyphenyl | Ethylamine | - | |
3'-HO-PCE | m -hydroxyphenyl | Ethylamine | - | |
3'-MeO-PCPr | m -methoxyphenyl | n -propylamine | - | |
3'-HO-PCPr | m -hydroxyphenyl | n -propylamine | - | |
3 ', 4'-MD-PCPr | 3,4-methylenedioxyphenyl | n -propylamine | - | |
3'-MeO-PCPy | m -methoxyphenyl | Pyrrolidine | - | |
4'-HO-PCP | p -hydroxyphenyl | Piperidine | - | |
Methoxydine (4'-MeO-PCP) | p -methoxyphenyl | Piperidine | - | |
4'-MeO-PCE | p -methoxyphenyl | Ethylamine | - | |
4'-F-PCP | p -fluorophenyl | Piperidine | - | |
4'-F-PCPy | p -fluorophenyl | Pyrrolidine | - | |
Arketamine | o -chlorophenyl | Methylamine | 2-oxo | |
Deschloroketamine | Phenyl | Methylamine | 2-oxo | |
Esketamine | o -chlorophenyl | Methylamine | 2-oxo | |
Ketamine | o -chlorophenyl | Methylamine | 2-oxo | |
Hydroxynorketamine | o -chlorophenyl | NH 2 | 2-oxo, 6-hydroxy | |
Ethketamine | o -chlorophenyl | Ethylamine | 2-oxo | |
NPNK | o -chlorophenyl | n -propylamine | 2-oxo | |
Methoxyketamine | o -methoxyphenyl | Methylamine | 2-oxo | |
oMDCK | o -Tolyl | Methylamine | 2-oxo | |
mMDCK | m -Tolyl | Methylamine | 2-oxo | |
meta- ketamine | m -chlorophenyl | Methylamine | 2-oxo | |
iso -ketamines | o -chlorophenyl | Methylamine | 4-oxo | |
2-fluorodeschloroketamine | o -fluorophenyl | Methylamine | 2-oxo | |
3-fluorodeschloroketamine | m -fluorophenyl | Methylamine | 2-oxo | |
Bromoketamine | o -Bromophenyl | Methylamine | 2-oxo | |
TFMDCK | o -trifluoromethylphenyl | Methylamine | 2-oxo | |
SN 35210 | o -chlorophenyl | Carbomethoxybutylamine | 2-oxo | |
Methoxetamine (MXE) | m -methoxyphenyl | Ethylamine | 2-oxo | |
Methoxmetamine | m -methoxyphenyl | Methylamine | 2-oxo | |
MXPr | m -methoxyphenyl | n -propylamine | 2-oxo | |
HXE | m -hydroxyphenyl | Ethylamine | 2-oxo | |
HXM | m -hydroxyphenyl | Methylamine | 2-oxo | |
FXE | m -fluorophenyl | Ethylamine | 2-oxo | |
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 (2'-MeO-PCMo) | o -methoxyphenyl | Morpholine | - | |
3'-MeO-PCMo | m -methoxyphenyl | Morpholine | - | |
4'-MeO-PCMo | p -methoxyphenyl | Morpholine | - | |
Methyl-PCM (4'-Me-PCMo) | p -tolyl | Morpholine | - | |
Hydroxy-methyl-PCM | 2-methyl-4-hydroxyphenyl | Morpholine | - | |
PYCP | 2-pyridinyl | Piperidine | - | |
TCM | 2-thienyl | Methylamine | - | |
TCE | 2-thienyl | Ethylamine | - | |
TCPr | 2-thienyl | Propylamine | - | |
Tenocyclidine (TCP) | 2-thienyl | Piperidine | - | |
TCPy | 2-thienyl | Pyrrolidine | - | |
Tiletamine | 2-thienyl | Ethylamine | 2-oxo | |
Gacyclidine | 2-thienyl | Piperidine | 2-methyl | |
BDPC | p -bromophenyl | Dimethylamine | 4-phenethyl-4-hydroxy | |
C-8813 | p -bromophenyl | Dimethylamine | 4- (thiophen-2-yl) ethyl-4-hydroxy | |
Dimetamine | p -tolyl | Dimethylamine | 4-oxo | |
3 "-OH-2'-Me-PCP | o -Tolyl | 3-hydroxypiperidine | - | |
4 "- Ph-4" - OH-PCP | Phenyl | 4-phenyl-4-hydroxypiperidine | - | |
BTCP | Benzothiophen-2-yl | Piperidine | - | |
BTCPy | Benzothiophen-2-yl | Pyrrolidine | - |
Analog connections
The structure dependence of the hallucinogenic effects of phencyclidine was investigated by varying the size of the cycloalkane ring. It turns out that the corresponding cyclopentyl compound has about 1/10 of the hallucinogenic activity, while the cycloheptyl and cyclooctyl derivatives are inactive. The homologous compounds are obtained by reacting the respective cycloalkyl ketones with phenylmagnesium bromide . The resulting alcohol is then reacted with sodium azide and then reduced to the amine with lithium aluminum hydride . In the last step the piperidine ring is then built up with 1-5-dibromopentane.
Web links
- H Morris, J Wallach: From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs . In: Drug Test Anal . 6, No. 7-8, 2014, pp. 614-32. doi : 10.1002 / dta.1620 . PMID 24678061 .
- Synthesis and Effects of PCP Analogs
- Interview with a Ketamine Chemist
Individual evidence
- ^ H. Morris, J. Wallach: From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs . In: Drug Testing and Analysis . 6, No. 7-8, 2014, pp. 614-32. doi : 10.1002 / dta.1620 . PMID 24678061 .
- ^ Jason Wallach, Simon D. Brandt: Phencyclidine-Based New Psychoactive Substances . In: Hans H. Maurer, Simon D. Brandt (Eds.): New Psychoactive Substances. Handbook of Experimental Pharmacology . tape 252 . Springer, Cham 2018, ISBN 978-3-03010560-0 , pp. 261-303 .
- ↑ Jason Wallach, Simon D. Brandt: 1,2-Diarylethylamine- and Ketamine-Based New Psychoactive Substances . In: Hans H. Maurer, Simon D. Brandt (Eds.): New Psychoactive Substances. Handbook of Experimental Pharmacology . tape 252 . Springer, Cham 2018, ISBN 978-3-03010560-0 , pp. 305-352 .
- ↑ a b c Abbas Ahmadi, Ali Mahmoudi: Synthesis and Biological Properties of 2-Hydroxy-1- (1-phenyltetralyl) piperidine and Some of its Intermediates as Derivatives of Phencyclidine . In: drug research . tape 55 , no. September 09 , 2005, p. 528 , doi : 10.1055 / s-0031-1296900 .
- ↑ a b c Abbas Ahmadi, Ali Mahmoudi, Ramin Hajikhani, Moslem Naserbakht: New morpholine analogues of phencyclidine: Chemical synthesis and pain perception in rats . In: Pharmacology Biochemistry and Behavior . tape 98 , no. 2 , April 2011, p. 227–233 , doi : 10.1016 / j.pbb.2010.12.019 .
- ↑ a b Isabelle Chaudieu, Jacques Vignon, Michèle Chicheportiche, Jean-Marc Kamenka, Gérard Trouiller, Robert Chicheportiche: Role of the aromatic group in the inhibition of phencyclidine binding and dopamine uptake by PCP analogs . In: Pharmacology Biochemistry and Behavior . tape 32 , no. 3 , March 1989, p. 699 , doi : 10.1016 / 0091-3057 (89) 90020-8 .
- ^ Y. Itzhak, Simon: A novel phencyclidine analog interacts selectively with mu opioid receptors . In: The Journal of Pharmacology and Experimental Therapeutics . 230, No. 2, 1984, pp. 383-386. PMID 6086884 .
- ↑ XS He, LP Raymon: Synthesis and biological evaluation of 1-1- (2-benzobthienyl) cyclohexylpiperidine homologues at dopamine-uptake and phencyclidine and sigma-binding sites . In: Journal of Medicinal Chemistry . 36, No. 9, 1993, pp. 1188-1193. doi : 10.1021 / jm00061a009 . PMID 8098066 .
- ↑ VA Eterović, R. Lu: Determinants of phencyclidine potency on the nicotinic acetylcholine receptors from muscle and electric organ . In: Cellular and Molecular Neurobiology . 19, No. 6, 1999, pp. 745-757. doi : 10.1023 / A: 1006905106834 . PMID 10456235 .
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- ^ OA al-Deeb: New analgesics derived from the phencyclidine analogue thienylcyclidine . In: drug research . 46, No. 5, May 1996, pp. 505-8. PMID 8737636 .
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- ↑ A Ahmadi: 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 . In: drug research . 59, No. 4, September, pp. 202-6. PMID 19517897 .
- ↑ A Ahmadi: Synthesis and pain perception of new analogues of phencyclidine in NMRI male mice . In: Mini Reviews in Medicinal Chemistry . 14, No. 1, September, pp. 64-71. PMID 24251803 .
- ↑ A Ahmadi: Synthesis and analgesic effects of new pyrrole derivatives of phencyclidine in mice . In: drug research . 61, No. 5, September, pp. 296-300. PMID 21755813 .
- ↑ A Ahmadi: Synthesis and determination of chronic and acute thermal and chemical pain activities of a new derivative of phencyclidine in rats . In: Iranian Journal of Pharmaceutical Research . 9, No. 4, September, pp. 379-85. PMID 24381602 .
- ↑ A Ahmadi: 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 . In: drug research . 60, No. 1, September, pp. 30-5. PMID 20184224 .
- ↑ R Hajikhani: Effect of phencyclidine derivatives on anxiety-like behavior using at elevated plus maze test in mice . In: Advances in Clinical and Experimental Medicine . 21, No. 3, September, pp. 307-12. PMID 23214193 .
- ↑ A Ahmadi: Synthesis and Antinociception Activities of Some Novel Derivatives of Phencyclidine with Substituted Aminobenzothiazoles . In: Mini Rev Med Chem . 17, No. 1, September, pp. 78-84. PMID 27121715 .
- ↑ D. Lednicer: 4- (p-Bromophenyl) -4- (dimethylamino) -1-phenethylcyclohexanol, an extremely potent representative of a new analgesic series . In: Journal of Medicinal Chemistry . 22, No. 10, September, pp. 1157-1158. PMID 513062 .
- ↑ T. Maurice: PRE-084, a sigma selective PCP derivative, attenuates MK-801-induced impairment of learning in mice . In: Pharmacology Biochemistry and Behavior . 49, No. 4, September, pp. 859-869. PMID 7886099 .
- ↑ A. Thurkauf, B. De Costa, S. Yamaguchi, MV Mattson, AE Jacobson, KC Rice, MA Rogawski: Synthesis and anticonvulsant activity of 1-phenylcyclohexylamine analogs . In: Journal of Medicinal Chemistry . 33, No. 5, 1990, pp. 1452-8. doi : 10.1021 / jm00167a027 . PMID 2329567 .
- ↑ C. Sauer, F. Peters, R. Staack, G. Fritschi, H. Maurer: Metabolism and toxicological detection of a new designer drug, N- (1-phenylcyclohexyl) propanamine, in rat urine using gas chromatography-mass spectrometry . In: Journal of Chromatography A . 1186, No. 1-2, 2008, pp. 380-390. doi : 10.1016 / j.chroma.2007.11.002 . PMID 18035363 .
- ↑ A Kalir, S Teomy, A Amir, P Fuchs, SA Lee, EJ Holsztynska, W Rocki: N-allyl analogues of phencyclidine: chemical synthesis and pharmacological properties . In: J Med Chem . 27, No. 10, September, pp. 1267-71. doi : 10.1021 / jm00376a006 . PMID 6481761 .
- ↑ C. Sauer, F. Peters, A. Schwaninger, M. Meyer, H. Maurer: 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 . In: Biochemical Pharmacology . 77, No. 3, 2009, pp. 444-450. doi : 10.1016 / j.bcp.2008.10.024 . PMID 19022226 .
- ^ MA Iorio, L. Tomassini, MV Mattson, C. George, AE Jacobson: 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 . In: Journal of Medicinal Chemistry . 34, No. 8, 1991, pp. 2615-2623. doi : 10.1021 / jm00112a041 . PMID 1875352 .
- ↑ A. Ahmadi, A. Mahmoudi: Synthesis with improved yield and study on the analgesic effect of 2-methoxyphencyclidine . In: drug research . 56, No. 5, 2006, pp. 346-350. doi : 10.1055 / s-0031-1296732 . PMID 16821645 .
- ↑ AM Ogunbadeniyi, A. Adejare: Syntheses of fluorinated phencyclidine analogs . In: Journal of Fluorine Chemistry . 114, 2002, pp. 39-42. doi : 10.1016 / S0022-1139 (01) 00565-6 .
- ^ J. Wallach, GD Paoli, A. Adejare, SD Brandt: Preparation and analytical characterization of 1- (1-phenylcyclohexyl) piperidine (PCP) and 1- (1-phenylcyclohexyl) pyrrolidine (PCPy) analogues . In: Drug Testing and Analysis . 6, No. 7-8, 2013, pp. 633-50. doi : 10.1002 / dta.1468 . PMID 23554350 .
- ↑ M Harvey, J Sleigh, L Voss, F Pruijn, J Jose, S Gamage, W Denny: Determination of the Hypnotic Potency in Rats of the Novel Ketamine Ester Analogue SN 35210 . In: Pharmacology . 96, No. 5-6, 2015, pp. 226-32. doi : 10.1159 / 000439598 . PMID 26352278 .
- ↑ Synthesis and determination of acute and chronic pain activities of 1- [1- (4-methylphenyl) (cyclohexyl)] morpholine as a new phencyclidine derivative in rats . In: drug research . 61, No. 2, 2011, pp. 92-7. doi : 10.1055 / s-0031-1296173 . PMID 21428243 .
- ↑ P Zarantonello, E Bettini, A Paio, C Simoncelli, S Terreni, F Cardullo: Novel analogues of ketamine and phencyclidine as NMDA receptor antagonists . In: Bioorg Med Chem Lett . 21, No. 7, September, pp. 2059-63. doi : 10.1016 / j.bmcl.2011.02.009 . PMID 21334205 .
- ↑ J Wallach, T Cole floor, B Cicali, SP Elliott, PV Kavanagh, A Adejare, NM Dempster: Syntheses and analytical characterizations of N-alkyl-arylcyclohexylamines . In: Drug Test Anal . 8, No. 8, 2016, pp. 801–815. doi : 10.1002 / dta.1861 . PMID 26360516 .
- ↑ D Lednicer, PF VonVoigtlander, DE Emmert: 4-Amino-4-arylcyclohexanones and their derivatives, a novel class of analgesics. 1. Modification of the aryl ring . In: J Med Chem . 23, No. 4, September, pp. 424-30. doi : 10.1021 / jm00178a014 . PMID 7381841 .
- ↑ A Ahmadi, J Solati, R Hajikhani, M Onagh, M Javadi: Synthesis and analgesic effects of 1-1- (2-methylphenyl) (cyclohexyl) -3-piperidinol as a new derivative of phencyclidine in mice . In: drug research . 60, No. 8, 2010, pp. 492-6. doi : 10.1055 / s-0031-1296317 . PMID 20863005 .
- ↑ Y Itzhak, A Kalir, BA Weissman, S Cohen: New analgesic drugs derived from phencyclidine . In: J Med Chem . 24, No. 5, 1981, pp. 496-9. doi : 10.1021 / jm00137a004 . PMID 7241506 .
- Jump up ↑ J. Vignon, V. Pinet, C. Cerruti, JM Kamenka, R. Chicheportiche: 3HN-1- (2-benzo (b) thiophenyl) cyclohexylpiperidine (3HBTCP): A new phencyclidine analog selective for the dopamine uptake complex . In: European Journal of Pharmacology . 148, No. 3, 1988, pp. 427-436. doi : 10.1016 / 0014-2999 (88) 90122-7 . PMID 3384005 .
- ↑ XS He, LP Raymon, MV Mattson, ME Eldefrawi, BR de Costa: Synthesis and biological evaluation of 1- [1- (2-benzo [b] thienyl) cyclohexyl] piperidine homologues at dopamine-uptake and phencyclidine- and sigma- binding sites . In: J Med Chem . 36, No. 9, September, pp. 1188-93. doi : 10.1021 / jm00061a009 . PMID 8098066 .
- ^ Roy L. McQuinn, Edward J. Cone, Harlan E. Shannon, Tsung-Ping Su: Structure-activity relationships of the cycloalkyl ring of phencyclidine . In: Journal of Medicinal Chemistry . tape 24 , no. December 12 , 1981, pp. 1429 , doi : 10.1021 / jm00144a011 .