Binding properties of [H-3]gacyclidine (cis(pip/me)-1-[1-(2-thienyl)-2-methylcyclohexyl]piperidine) enantiomers in the rat central nervous system

Gacyclidine (cis(pip/me)-1-[1-(2-thienyl)-2-methylcyclohexyl]piperidine) is a TCP derivative, which exhibits potent neuroprotective properties against glutamate-induced neurotoxicity in vitro and in vivo. In order to better u nderstand gacyclidine pharmacological properties. the binding parameters of its enantiomers ((-) and (+)[H-3]GK11) were determined in the rat central nervous system (CNS). An autoradiographic study has shown that their bindin g distributions are correlated with those of N-methyl-D-aspartate (NMDA) re ceptors throughout the CNS. Globally, the labeling was the highest with (-) [H-3]GK11. Tn the cerebellum, both radioligands similarly labeled the molec ular layer. For both radioligands, on telencephalic, cerebellum and spinal cord homogenates, the association and dissociation kinetics were accounted for by multiphasic process. In all regions, (-)[H-3]GK11 exhibited the high est affinity in the nanomolar range. The pharmacological study revealed tha t both enantiomers labeled both high and low affinity sites in all regions. The pharmacological profile of high affinity sites was correlated with tho se of NMDA receptors. Those of low affinity sites were different in telence phalic and cerebellar homogenates. Overall, this study showed that low affi nity sites might constitute a heterogeneous population, which could include sigma receptors in the cerebellum. The autoradiographic study has shown th at these sites may be located in the molecular layer. The contribution of l ow affinity sites to the neuroprotective properties of gacyclidine remains to be investigated. (C) 2000 Elsevier Science B.V. All rights reserved.