Arylcyclohexylamine
Class of chemical compounds
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
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 D 2 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 D 2 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.
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 [24] | Phenyl | NH 2 | - | 1934-71-0 | |
PCM [24] | Phenyl | Methylamino | - | 2201-16-3 | |
Eticyclidine | Phenyl | Ethylamino | - | 2201-15-2 | |
PCPr [25] | Phenyl | n -Propylamino | - | 18949-81-0 | |
PCiP | Phenyl | Isopropylamino | - | 1195-42-2 | |
PCAL [26] | Phenyl | Allylamino | - | 2185-95-7 | |
PCBu | Phenyl | n -Butylamino | - | 73166-29-7 | |
PCEOH | Phenyl | Hydroxyethylamino | - | 2201-22-1 | |
PCMEA [27] | Phenyl | Methoxyethylamino | - | 2201-57-2 | |
PCEEA | Phenyl | Ethoxyethylamino | - | 1072895-05-6 | |
PCMPA | Phenyl | Methoxypropylamino | - | 2201-58-3 | |
PCDM [24] | Phenyl | Dimethylamino | - | 2201-17-4 | |
Dieticyclidine | Phenyl | Diethylamino | - | 2201-19-6 | |
2-HO-PCP [6] | Phenyl | Piperidine | 2-Hydroxy | 94852-58-1 | |
2-Me-PCP [28] | Phenyl | Piperidine | 2-Methyl | 59397-29-4 | |
2-MeO-PCP [29] | Phenyl | Piperidine | 2-Methoxy | 78636-34-7 | |
2-Keto-PCP | Phenyl | Piperidine | 2-Keto | 101688-16-8 | |
Eticyclidone ("O-PCE") | Phenyl | Ethylamino | 2-Keto | 6740-82-5 | |
2-Keto-PCPr | Phenyl | n -Propylamino | 2-Keto | ||
4-Methyl-PCP | Phenyl | Piperidine | 4-Methyl | 19420-52-1 | |
4-Keto-PCP [30] | Phenyl | Piperidine | 4-Keto | 65620-13-5 | |
2'-Cl-PCP | o -Chlorophenyl | Piperidine | - | 2201-31-2 | |
3'-Cl-PCP | m -Chlorophenyl | Piperidine | - | 2201-32-3 | |
2'-MeO-PCP | o -Methoxyphenyl | Piperidine | - | 2201-34-5 | |
3'-F-PCP [31] | m -Fluorophenyl | Piperidine | - | 89156-99-0 | |
3'-Me-PCP [32] | m -Tolyl | Piperidine | - | 2201-30-1 | |
3'-Me-PCPy | m -Tolyl | Pyrrolidine | - | 1622348-63-3 | |
3'-NH 2 -PCP | m -Aminophenyl | Piperidine | - | 72242-00-3 | |
3'-HO-PCP | m -Hydroxyphenyl | Piperidine | - | 79787-43-2 | |
3'-MeO-PCP | m -Methoxyphenyl | Piperidine | - | 72242-03-6 | |
3',4'-MD-PCP | 3,4-Methylenedioxyphenyl | Piperidine | - | ||
3'-MeO-PCE | m -Methoxyphenyl | Ethylamino | - | 1364933-80-1 | |
3'-HO-PCE | m -Hydroxyphenyl | Ethylamino | - | ||
3'-MeO-PCPr | m -Methoxyphenyl | n -Propylamino | - | 1364933-81-2 | |
3'-HO-PCPr | m -Hydroxyphenyl | n -Propylamino | - | ||
3',4'-MD-PCPr | 3,4-Methylenedioxyphenyl | n -Propylamino | - | ||
3'-MeO-PCPy [32] | m -Methoxyphenyl | Pyrrolidine | - | 1364933-79-8 | |
4'-HO-PCP | p -Hydroxyphenyl | Piperidine | - | 66568-88-5 | |
Methoxydine (4'-MeO-PCP) | p -Methoxyphenyl | Piperidine | - | 2201-35-6 | |
4'-MeO-PCE | p -Methoxyphenyl | Ethylamino | - | ||
4'-F-PCP [31] | p -Fluorophenyl | Piperidine | - | 22904-99-0 | |
4'-F-PCPy | p -Fluorophenyl | Pyrrolidine | - | ||
Arketamine | o -Chlorophenyl | Methylamino | 2-Keto | 33643-49-1 | |
Deschloroketamine | Phenyl | Methylamino | 2-Keto | 7063-30-1 | |
Esketamine | o -Chlorophenyl | Methylamino | 2-Keto | 33643-46-8 | |
Ketamine | o -Chlorophenyl | Methylamino | 2-Keto | 6740-88-1 | |
Hydroxynorketamine | o -Chlorophenyl | NH 2 | 2-Keto, 6-Hydroxy | 81395-70-2 | |
Ethketamine | o -Chlorophenyl | Ethylamino | 2-Keto | 1354634-10-8 | |
NPNK | o -Chlorophenyl | n -Propylamino | 2-Keto | 2749326-65-4 | |
Methoxyketamine | o -Methoxyphenyl | Methylamino | 2-Keto | 7063-51-6 | |
2-MeO-NEK [33] | o -Methoxyphenyl | Ethylamino | 2-Keto | ||
oMDCK [34] | o -Tolyl | Methylamino | 2-Keto | 7063-37-8 | |
mMDCK | m -Tolyl | Methylamino | 2-Keto | ||
meta -Ketamine | m -Chlorophenyl | Methylamino | 2-Keto | 7063-53-8 | |
iso -Ketamine | o -Chlorophenyl | Methylamino | 4-Keto | ||
2-Fluorodeschloroketamine | o -Fluorophenyl | Methylamino | 2-Keto | 111982-50-4 | |
3-Fluorodeschloroketamine | m -Fluorophenyl | Methylamino | 2-Keto | 2657761-23-2 | |
Bromoketamine | o -Bromophenyl | Methylamino | 2-Keto | 120807-70-7 | |
TFMDCK | o -Trifluoromethylphenyl | Methylamino | 2-Keto | 1782149-73-8 | |
SN 35210 [35] | o -Chlorophenyl | Carbomethoxybutylamino | 2-Keto | 1450615-41-4 | |
Methoxetamine | m -Methoxyphenyl | Ethylamino | 2-Keto | 1239943-76-0 | |
Methoxmetamine | m -Methoxyphenyl | Methylamino | 2-Keto | 1781829-56-8 | |
Methoxpropamine | m -Methoxyphenyl | n -Propylamino | 2-Keto | 2504100-71-2 | |
MXiPr | m -Methoxyphenyl | i -Propylamino | 2-Keto | ||
Ethoxetamine | m -Ethoxyphenyl | Ethylamino | 2-Keto | ||
Deoxymethoxetamine (3-Me-2'-Oxo-PCE) | m -Tolyl | Ethylamino | 2-Keto | 2666932-45-0 | |
Br-MXE | 2-bromo-5-methoxyphenyl | Ethylamino | 2-Keto | ||
Hydroxetamine (HXE) | m -Hydroxyphenyl | Ethylamino | 2-Keto | 1620054-73-0 | |
HXM | m -Hydroxyphenyl | Methylamino | 2-Keto | ||
Fluorexetamine (FXE) | m -Fluorophenyl | Ethylamino | 2-Keto | ||
Phencyclidine (PCP) | Phenyl | Piperidine | - | 77-10-1 | |
PC3MP | Phenyl | 3-Methylpiperidine | - | 2201-41-4 | |
PC4MP | Phenyl | 4-Methylpiperidine | - | 2201-42-5 | |
Rolicyclidine (PCPy) | Phenyl | Pyrrolidine | - | 2201-39-0 | |
PCDMPy | Phenyl | 3,3-Dimethylpyrrolidine | - | ||
PCMo | Phenyl | Morpholine | - | 2201-40-3 | |
Methoxy-PCM [7] (2'-MeO-PCMo) | o -Methoxyphenyl | Morpholine | - | 1314323-88-0 | |
3'-MeO-PCMo | m -Methoxyphenyl | Morpholine | - | 138873-80-0 | |
4'-MeO-PCMo | p -Methoxyphenyl | Morpholine | - | ||
Methyl-PCM [36] (4'-Me-PCMo) | p -Tolyl | Morpholine | - | 120803-52-3 | |
Hydroxy-methyl-PCM | 2-Methyl-4-hydroxyphenyl | Morpholine | - | 1314323-89-1 | |
PYCP [37] | 2-Pyridinyl | Piperidine | - | ||
TCM | 2-Thienyl | Methylamino | - | 139401-07-3 | |
TCE | 2-Thienyl | Ethylamino | - | 101589-62-2 | |
TCPr [38] | 2-Thienyl | Propylamino | - | ||
Tenocyclidine (TCP) | 2-Thienyl | Piperidine | - | 21500-98-1 | |
T3CP | 3-Thienyl | Piperidine | - | 19420-50-9 | |
TCPy | 2-Thienyl | Pyrrolidine | - | 22912-13-6 | |
Tiletamine | 2-Thienyl | Ethylamino | 2-Keto | 14176-49-9 | |
MXTE | 4-Methoxy-2-thienyl | Ethylamino | 2-Keto | ||
Gacyclidine | 2-Thienyl | Piperidine | 2-Methyl | 68134-81-6 | |
BDPC | p -Bromophenyl | Dimethylamino | 4-Phenethyl-4-hydroxy | 77239-98-6 | |
C-8813 | p -Bromophenyl | Dimethylamino | 4-(thiophen-2-yl)ethyl-4-hydroxy | 616898-54-5 | |
Dimetamine [39] | p -Tolyl | Dimethylamino | 4-Keto | 65619-06-9 | |
3''-OH-2'-Me-PCP [40] | o -Tolyl | 3-Hydroxypiperidine | - | ||
4''-Ph-4''-OH-PCP [41] | Phenyl | 4-Phenyl-4-hydroxypiperidine | - | 77179-39-6 | |
BTCP [42] | Benzothiophen-2-yl | Piperidine | - | 112726-66-6 | |
BTCPy [10] | Benzothiophen-2-yl | Pyrrolidine | - | ||
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 NaN 3 ; 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 | Phenyl | Piperidine | Cyclopentyl | 23036-19-3 | |
3F-PCHEPy | 3-Fluorophenyl | Pyrrolidine | Cycloheptyl | ||
3-MeO-PBCHP | 3-Methoxyphenyl | Piperidine | Bicyclo[2.2.1]heptane | ||
PADP (P2AP) | Phenyl | Piperidine | Adamantyl | 72241-99-7 | |
3-MeO-PTP | 3-Methoxyphenyl | Piperidine | Tetralin | ||
HHFA | Fused phenyl | Amino | Hexahydrofluorene | ||
DHPQ | Phenyl | Decahydroquinoline | |||
POXP | Phenyl | Piperidine | Oxane | ||
PTHP | Phenyl | Piperidine | Thiane | ||
MPBPip | Phenyl | Piperidine | N-Methylpiperidine | 36882-04-9 | |
BnCP | Benzyl | Piperidine | Cyclohexyl | 22912-07-8 | |
YNCP | Ethynyl | Piperidine | Cyclohexyl | 51165-02-7 | |
ALCP | Allyl | Piperidine | Cyclohexyl | 7418-80-6 | |
Piritramide | Replaced by carboxamide | Piperidine | N-(3-cyano-3,3-diphenylpropyl)piperidine | 302-41-0 | |
PRE-084 | Phenyl | Morpholinylethylcarboxylate | Cyclohexyl | 138847-85-5 | |
Clofenciclan | p-Chlorophenyl | Diethylaminoethoxy | Cyclohexyl | 5632-52-0 | |
References
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- ↑ Harvey M, Sleigh J, Voss L, Pruijn F, Jose J, Gamage S, Denny W (2015). "Determination of the Hypnotic Potency in Rats of the Novel Ketamine Ester Analogue SN 35210". Pharmacology . 96 (5–6): 226–32. doi : 10.1159/000439598 . PMID 26352278 . S2CID 36017002 .
- ↑ 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. doi : 10.1055/s-0031-1296173 . PMID 21428243 . S2CID 8094521 .
- ↑ Zarantonello P, Bettini E, Paio A, Simoncelli C, Terreni S, Cardullo F (April 2011). "Novel analogues of ketamine and phencyclidine as NMDA receptor antagonists". Bioorganic & Medicinal Chemistry Letters . 21 (7): 2059–63. doi : 10.1016/j.bmcl.2011.02.009 . PMID 21334205 .
- ↑ Wallach J, Colestock T, Cicali B, Elliott SP, Kavanagh PV, Adejare A, et al. (August 2016). "Syntheses and analytical characterizations of N-alkyl-arylcyclohexylamines" (PDF) . Drug Testing and Analysis . 8 (8): 801–15. doi : 10.1002/dta.1861 . PMID 26360516 . S2CID 1599386 .
- ↑ Lednicer D, VonVoigtlander PF, Emmert DE (April 1980). "4-Amino-4-arylcyclohexanones and their derivatives, a novel class of analgesics. 1. Modification of the aryl ring". Journal of Medicinal Chemistry . 23 (4): 424–30. doi : 10.1021/jm00178a014 . PMID 7381841 .
- ↑ Ahmadi A, Solati J, Hajikhani R, Onagh M, Javadi M (2010). "Synthesis and analgesic effects of 1-[1-(2-methylphenyl)(cyclohexyl)]-3-piperidinol as a new derivative of phencyclidine in mice". Arzneimittel-Forschung . 60 (8): 492–6. doi : 10.1055/s-0031-1296317 . PMID 20863005 . S2CID 24803623 .
- ↑ Itzhak Y, Kalir A, Weissman BA, Cohen S (May 1981). "New analgesic drugs derived from phencyclidine". Journal of Medicinal Chemistry . 24 (5): 496–9. doi : 10.1021/jm00137a004 . PMID 7241506 .
- ↑ Vignon J, Pinet V, Cerruti C, Kamenka JM, Chicheportiche R (April 1988). "[3H]N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine ([3H]BTCP): a new phencyclidine analog selective for the dopamine uptake complex". European Journal of Pharmacology . 148 (3): 427–36. doi : 10.1016/0014-2999(88)90122-7 . PMID 3384005 .
- ↑ Kamenka JM, et al. Substituted cyclic amines and pharmaceutical composition containing them. Patent US5248686, 28 September 1993
- ↑ 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.
- ↑ Shulgin AT, Mac Lean DE (1976). "Illicit synthesis of phencyclidine (PCP) and several of its analogs". Clinical Toxicology . 9 (4): 553–60. doi : 10.3109/15563657608988157 . PMID 975751 .
- ↑ Sun S, Wallach J, Adejare A (2014). "Syntheses and N-methyl-D-aspartate receptor antagonist pharmacology of fluorinated arylcycloheptylamines". Medicinal Chemistry . Shariqah (United Arab Emirates). 10 (8): 843–52. doi : 10.2174/1573406410666140428104444 . PMID 24773376 .
- ↑ McQuinn RL, Cone EJ, Shannon HE, Su TP (December 1981). "Structure-activity relationships of the cycloalkyl ring of phencyclidine". Journal of Medicinal Chemistry . 24 (12): 1429–32. doi : 10.1021/jm00144a011 . PMID 7310819 .
- ↑ Eaton TA, Houk KN, Watkins SF, Fronczek FR (April 1983). "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. doi : 10.1021/jm00358a005 . PMID 6834381 .
- ↑ Sisco E, Urbas A. Identification and Characterization of Designer Phencyclidines (PCPs) in Forensic Casework
- ↑ Gerhard O, Eberhard E. 4-amino-piperidines. US3311624A
- ↑ Moriarty RM, Enache LA, Zhao L, Gilardi R, Mattson MV, Prakash O (February 1998). "Rigid phencyclidine analogues. Binding to the phencyclidine and sigma 1 receptors". Journal of Medicinal Chemistry . 41 (4): 468–77. doi : 10.1021/jm970059p . PMID 9484497 .
Further reading
- Morris H, Wallach J (2014). "From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs". Drug Testing and Analysis . 6 (7–8): 614–32. doi : 10.1002/dta.1620 . PMID 24678061 .
External links
- Synthesis and Effects of PCP Analogs
- Interview with a Ketamine Chemist
- New Drugs: Designing Novel Arylcyclohexylamines
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