CP-101,606, A POTENT NEUROPROTECTANT SELECTIVE FOR FOREBRAIN NEURONS

The neuroprotective activity of henyl)-2-(4-hydroxy-4-phenylpiperidino )-1-propanol (CP-101,606), an N-methyl-D-aspartate (NMDA) receptor ant agonist structurally similar to ha-(4-hydroxyphenyI)-beta-methyl-4-(ph enylmethyl)- 1-piperidineethanol (ifenprodil), was investigated in neu rons in primary culture. CP-101,606 potently and efficaciously protect ed hippocampal neurons from glutamate toxicity but was > 900-fold less effective for cerebellar granule neurons. The neuroprotective activit y in the hippocampal neurons is mediated through a high affinity bindi ng site distinct from the agonist and thienylcyclohexylpiperidine (TCP ) binding sites of the NMDA receptor. Autoradiography indicates the CP -101,606 binding site is localized in forebrain, most notably in hippo campus and the outer layers of cortex. The functional selectivity for hippocampal neurons, forebrain localization of binding sites, and stru ctural relation to ifenprodil suggest that CP-101,606 is an NMDA antag onist highly selective for NR2B subunit containing receptors. (C) 1997 Elsevier Science B.V.