HOMOCHIRAL STRUCTURES DERIVED FROM 1-[1-(2-THIENYL)CYCLOHEXYL]PIPERIDINE (TCP) ARE POTENT NONCOMPETITIVE ANTAGONISTS OF GLUTAMATE AT NMDA RECEPTOR-SITES

The racemates of cis (pip/Me) 1-[1-(2-thienyl)-2-methylcyclohexyl]pipe and cis (pip/Me) 1-[1-(2-furanyl)-2-methylcyclohexyl]piperidine, 2 de rivatives of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) have been synthesized. Th e corresponding isomers were resolved by a crystallization procedure, via the diastereoisomeric salts formed with (+)- and (-)-di-O,O'-4-tol uoyltartaric acid. The absolute configuration was determined by single -crystal X-ray analysis and by comparison with previously published da ta in related series. The 4 homochiral structures obtained were tested for their affinity for the PCP receptor sites labelled with [H-3]TCP. Their neuroprotective potency was assessed in primary cultured neuron al cells against neurotoxicity induced by glutamate. The 2(-)-1S, 2R-i somers displayed the highest affinity for the PCP receptor sites and t he highest efficacy for neuronal protection in comparison with the (+) -1R, 2S-isomers.