NPC 16377, a potent and selective sigma-ligand. II. Behavioral and neuroprotective profile

6-[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCI, (NPC 16377), a potent and highly selective sigma-site ligand, was evaluated in tests predictive of antipsychotic and neuroprotective potential and for toxicity. Like haloperidol, clozapine and remoxipride, and the sigma-ligands BMY 14802, ifenprodil and rimcazole, NPC 16377 reversed amphetamine-induced hyperactivity and apomorphine-induced climbing in mice. Additional evidence for antipsychotic activity was obtained in rats with NPC 16377, clozapine, BMY 14802, ifenprodil, haloperidol and rimcazole, all of which reduced conditioned avoidance responses at doses that did not reduce escape behavior. NPC 16377 did not induce catalepsy in mice, suggesting a decreased liability for producing extrapyramidal side effects. NPC 16377 extended survival time for mice exposed to a hypoxic environment. In a model of global ischemia using conscious gerbils, NPC 16377 prevented damage to hippocampal CA1 neurons after either intraperitoneal or oral administration. NPC 16377 did not disrupt prepulse inhibition or block the disruption of prepulse inhibition induced by the phencyclidine site-selective ligand (+)MK-801. In rats trained to discriminate phencyclidine from saline, NPC 16377 did not substitute for the psychotomimetic. These data are consistent with the notion that selective sigma-agents may possess antipsychotic and neuroprotective activities. Moreover, the results from prepulse inhibition and drug discrimination experiments suggest that NPC 16377 is devoid of phencyclidine-like effects.