Synthesis and anticonvulsant activity of 1-phenylcyclohexylamine analogs

• Published in: Journal of medicinal chemistry Vol. 33; no. 5; pp. 1452 - 1458
• Main Authors: Thurkauf, Andrew, De Costa, Brian, Yamaguchi, Shunichi, Mattson, Mariena V, Jacobson, Arthur E, Rice, Kenner C, Rogawski, Michael A
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.05.1990
• Subjects: Animals; Anticonvulsants - chemical synthesis; Anticonvulsants. Antiepileptics. Antiparkinson agents; Binding Sites; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Chemical Phenomena; Chemistry; Cyclohexylamines - chemical synthesis; Cyclohexylamines - pharmacology; Electric Stimulation; Male; Medical sciences; Mice; Motor Activity - drug effects; Neuropharmacology; Pharmacology. Drug treatments; Phencyclidine - analogs & derivatives; Phencyclidine - pharmacology; Rodentia; Seizures - prevention & control; Structure-Activity Relationship; Brain; Nervous system diseases; Intraperitoneal administration; Rat; Toxicity; Epilepsy; Rodentia; Central nervous system; Anticonvulsant; In vitro; Prevention; In vivo; Vertebrata; Chemotherapy; Biological fixation; Experimental disease; Mammalia; Treatment; Structure activity relation; Animal; Chemical synthesis; Electroshock; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00167a027

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 5-41 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.