NPC-16377, A POTENT AND SELECTIVE SIGMA-LIGAND .2. BEHAVIORAL AND NEUROPROTECTIVE PROFILE

[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCl, (NPC 16377), a potent and highly selective sigma-site ligand, was evaluated in tests predictive of antipsychotic and neuroprotective potential and for tox icity. Like haloperidol, clozapine and remoxipride, and the sigma-liga nds BMY 14802, ifenprodil and rimcazole, NPC 16377 reversed amphetamin e-induced hyperactivity and apomorphine-induced climbing in mice. Addi tional evidence for antipsychotic activity was obtained in rats with N PC 16377, clozapine, BMY 14802, ifenprodil, haloperidol and rimcazole, all of which reduced conditioned avoidance responses at doses that di d not reduce escape behavior. NPC 16377 did not induce catalepsy in mi ce, suggesting a decreased liability for producing extrapyramidal side effects. NPC 16377 extended survival time for mice exposed to a hypox ic environment. In a model of global ischemia using conscious gerbils, NPC 16377 prevented damage to hippocampal CA1 neurons after either in traperitoneal or oral administration. NPC 16377 did not disrupt prepul se inhibition or block the disruption of prepulse inhibition induced b y the phencyclidine site-selective ligand (+)MK-801. In rats trained t o discriminate phencyclidine from saline, NPC 16377 did not substitute for the psychotomimetic. These data are consistent with the notion th at selective sigma-agents may possess antipsychotic and neuroprotectiv e activities. Moreover, the results from prepulse inhibition and drug discrimination experiments suggest that NPC 16377 is devoid of phencyc lidine-like effects.