List of refs.: 1) TITLE Synthesis and Anticonvulsant Activity of 1-Phenylcyclohexylamine Analogues AUTHORS Thurkauf, Andrew; Costa, Brian de; Yamaguchi, Shun-ichi; Mattson, Mariena V.; Jacobson, Arthur E.; et al. SOURCE J.Med.Chem. 1990, 33: 5 1452-1458 DOCUMENT TYPE Journal CODEN JMCMAR LANGUAGE EN CNR 5509129 ABSTRACT Thirty-eight analogues of 1-phenylcyclohexylamine (PCA), a phencyclidine (PCP) derivative, were examined for their activities in the mouse maximal electroshock (MES) seizure test and in a motor-toxicity assay.In addition, we determined the binding affinities of the compounds for PCP acceptor sites in rat brain membranes labeled with (3H)-1-(1-(2-thienyl)cyclohexyl)piperidine.Many of the analogues were protective against MES seizures (ED50s of 4-41 mg/kg, ip) and all of these compounds caused motor toxicity.The potencies in the motor toxicity and MES seizure tests showed a moderate correlation with the affinities for PCP sites.Several analogues exhibited a greater separation of potencies in the motor toxicity and MES seizure tests than did the parent compound PCA.These were obtained by (i) 3-methylation of the cyclohexyl ring trans to the phenyl ring, (ii) methoxylation at the ortho position on the phenyl ring, and (iii) contraction of the cyclohexane ring to form the corresponding cyclopentane =========================================================== 2) TITLE Synthesis, Pharmacological Action, and Receptor Binding Affinity of the Enantiomeric 1-(1-Phenyl-3-methylcyclohexyl)piperidines AUTHORS Thurkauf, Andrew; Hillery, Paul; Mattson, Mariena V.; Jacobson, Arthur E.; Rice, Kenner C. SOURCE J.Med.Chem. 1988, 31: 8 1625-1628 DOCUMENT TYPE Journal CODEN JMCMAR LANGUAGE EN CNR 5799729 ABSTRACT The cis and trans enantiomers of the 1-(1-phenyl-3-methylcyclohexyl)piperidines were prepared from either 3(R)- or 3(S)-methylcyclohexanone through the Bruylents reaction or a modified azide route, respectively.Separation of the intermediate amines 5 and 6 was achieved through chromatography or selective crystallization of a fumarate salt.The cis isomer 2b had about one-third of the affinity of phencyclidine for the PCP receptor.The other isomers were less potent.There was a 40-fold difference between the binding affinity of the cis enantiomers 2a and 2b and a fourfold difference between the affinities of the trans enantiomers 1a and 1b.None of the compounds antagonized the stereotypy induced by phencyclidine in the rotorod assay in mice, after intraperitoneal introduction. =========================================================== 3) TITLE N-Allyl Analogues of Phencyclidine: Chemical Synthesis and Pharmacological Properties AUTHORS Kalir, Asher; Teomy, Shoshana; Amir, Adina; Fuchs, P.; Lee, Sung A.; et al. SOURCE J.Med.Chem. 1984, 27: 10 1267-1271 DOCUMENT TYPE Journal CODEN JMCMAR LANGUAGE EN CNR 5804034 ABSTRACT Several N-allyl derivatives of 1-phenylcyclohexylamine (PCA) were prepared, and their pharmacology was briefly characterized.The mono- and diallyl derivatives 4-7 had phencyclidine-like activities in mice but were less potent behaviorally than phencyclidine (PCP).None were PCP antagonists.In vitro these compounds were competitive inhibitors of butyrylcholinesterase (BChE) and protected against inhibition by DFP.In addition, these agents displaced tritiated N-methyl-4-piperidyl benzilate from mouse-brain homogenates and inhibited the effects of acetylcholine on isolated guinea pig ileum.None of these in vitro effects correlated with their PCP-like behavioral activity in vivo in mice. ========================================================== 4) TITLE Chemical Synthesis and Molecular Pharmacology of Hydroxylated 1-(1-Phenylcyclohexyl)piperidine Derivatives AUTHORS Kamenka, J. M.; Chiche, B.; Goudal, R.; Geneste, P.; Vignon, J.; et al. SOURCE J.Med.Chem. 1982, 25: 4 431-435 DOCUMENT TYPE Journal CODEN JMCMAR LANGUAGE EN CNR 5640081 ABSTRACT The following monohydroxy derivatives of 1-(1-phenylcyclohexyl)piperidine (phencyclidine, PCP) were synthesized: o-, m-, and p-phenols of PCP, 1-(1-phenylcyclohexyl)-4-piperidinol, and two stereoisomersic pairs of 3-phenyl-3-(1-piperidinyl)cyclohexanol and 4-phenyl-4-(1- piperidinyl)cyclohexanol.Inhibition of specific binding of tritiated PCP, morphine, or quinuclidynyl benzylate (QNB) in rat brain homogenates was measured for these compounds.Inhibition of PCP binding for selected compounds correlated with mouse rotarod assay activity.The most characteristic effects of hydroxylation of PCP on the cyclohexyl, piperidine, or phenyl moieties are the following: (i) it generally decreases its activity in inhibiting (3H)PCP binding by a factor of 10 to 80; (ii) it does not produce a large variation in the affinity for the morphine receptor; (iii) it produces a considerable decrease of the affinity for the muscarinic receptor.An important exception to these general observations was the metaphenolic derivative of PCP.This PCP derivative has an affinity for the (3H)PCP binding sites that is 8 times higher than that of PCP itself; its affinity for the muscarinic receptor is only twice lower than that of PCP, but its affinity for the morphine receptor is 430 times higher than that of PCP and only one order of magnitude lower than that of morphine itself. ========================================================== 5) TITLE 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 AUTHORS Iorio, Maria A.; Tomassini, Lamberto; Mattson, Mariena V.; George, Clifford; Jacobson, Arthur E. SOURCE J.Med.Chem. 1991, 34: 8 2615-2623 DOCUMENT TYPE Journal CODEN JMCMAR LANGUAGE EN CNR 5581378 ABSTRACT The (-)- and (+)-isomers of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines have been synthesized and the achiral cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines were prepared, and their in vitro and in vivo (rotarod assay) activities determined.The 1- (1-phenyl-2-methylcyclohexyl)piperidine isomers were resolved by classical crystallization procedures, through the diasteromeric salts obtained with d- and l-10-camphorsulfonic acid.The relative stereochemistry of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines and the achiral cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines was established by using 13C and 1H NMR.Both (-)-trans-1-(1-phenyl-2- methylcyclohexyl)piperidine ((-)-2) and (+)-trans-1-(1-phenyl-2-methylcyclohexyl)piperidine ((+)-2) were examined by single-crystal X-ray analysis, and the absolute configuration of (-)-2 was determined to be 1S,2R.The (-)-2 was found to be about five times more potent than PCP in vitro and twice as potent in vivo.It is the most potent of all of the simple methyl-substituted cyclohexyl PCP isomers and is among the most potent PCP-like compounds which have been synthesized.It was nine times more potent in vitro and four times more potent in vivo than (+)-2.The racemic cis-1-(1-phenyl-2- methylcyclohexyl)piperidine (3), and its enantiomers ((+)-3 and (-)-3), were essentially inactive in vitro and in vivo.The cis-Ph/Me 1-(1-phenyl-4- methylcyclohexyl)piperidine (18) was more potent than trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidine (17), but considerably less potent than (- )-2.The enantioselectivity observed as the PCP binding site for (-)-2 could indicate that this site can discriminate between enantiotopic edges of the achiral PCP (choosing the pro-1-S edge), as does the ì-opioid receptor in the prodine series of opioids.Benzimidoyl or benzoyl group replacement of the phenyl ring in the 1-(1-phenyl-2-methylcyclohexyl)piperidine series gave compounds which showed little in vitro and in vivo activity. ========================================================== 6) TITLE New Analgesic Drugs Derived from Phencyclidine AUTHORS Itzhak, Yossef; Kalir, Asher; Weissman, Ben Avi; Cohen, Sasson SOURCE J.Med.Chem. 1981, 24: 5 496-499 DOCUMENT TYPE Journal CODEN JMCMAR LANGUAGE EN CNR 5638120 ABSTRACT Several esters of 1-(1-phenylcyclohexyl)-4-piperidinol (3), 1-(1-phenylcyclohexyl)-4-phenyl-4-piperidinol (10) and its propionate (11), and 1-(1-phenylcyclohexyl)-4-phenylpiperidine (13) were prepared and characterized.The new compounds, which are derived from phencyclidine, exerted analgesic activity in mice.The most potent is 10, which is twice as active as morphine.The antinociceptive activity of 10, 11, and 13 could be well correlated with their potency in the mouse vas deferens bioassay, and both were completely reversed by naloxone. ========================================================= 7) TITLE Structure-Activity Relationships of the Cycloalkyl Ring of Phencyclidine AUTHORS McQuinn, Roy L.; Cone, Edward J.; Shannon, Harlan E.; Su, Tsung-Ping SOURCE J.Med.Chem. 1981, 24: 12 1429-1432 DOCUMENT TYPE Journal CODEN JMCMAR LANGUAGE EN CNR 5638087 ABSTRACT In order to investigate the structural requirements for a cycloalkyl moiety in the potent hallucinogen 1-(1-phenylcyclohexyl)piperidine (PCP, 1), a series of structural analogues was synthesized in which the size of the cycloalkyl ring was varied from three carbons to eight carbons.Biological activities of these compounds were assessed in an in vitro assay (phencyclidine binding assay) and an in vivo assay (discriminative stimulus assay).As the cycloalkyl ring size decreased from that of cyclohexane (PCP), PCP-like activity declined in both assays, but as the cycloalkyl ring size became larger than cyclohexane, a sharp decline in PCP-like activity was observed in the in vivo assay, while activity in the in vitro assay was only slightly less than that of PCP. 1-(1-Phenylcyclooctyl)piperidine (8) had potent competitive binding properties in the in vitro binding assay but produced no observable PCP-like effects in the in vivo assay.The importance of the cycloalkyl ring in the structure of PCP was demonstrated by testing benzylpiperidine (2), which had almost no measurable activity in either assay.