NPC-16377, A POTENT AND SELECTIVE SIGMA-LIGAND .1. RECEPTOR-BINDING, NEUROCHEMICAL AND NEUROENDOCRINE PROFILE

[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCl (NPC 16377), a structurally novel compound, was found to be a highly potent and selec tive ligand for sigma-sites Although 5-fold less potent than haloperid ol and 2-fold less potent than ifenprodil to inhibit 1,3-di-o-tolylgua nidine binding, NPC 16377 (IC50 = 36 nM) was more potent than rophenyl )-4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl butanol (BMY 14802), rimcaz ole and the atypical antipsychotic, clozapine. A similar rank order of potency was observed when [H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)pi perdine was used as the radioligand. Like BMY, rimcazole and clozapine , NPC 16377 (IC50 = 2671 nM) had low affinity for dopamine type 2 rece ptors. Additionally, the compound was only weakly active in 35 additio nal receptor binding assays including those for serotonin2 and seroton in1C receptors. In vivo, NPC 16377 potently inhibited the binding of [ H-3]-(+)-N-allylnormetazocine to sigma sites after both intraperitonea l and oral administration. At doses 30-fold in excess of the ID50 to i nhibit [H-3] (+)N-allylnormetazocine, NPC 16377 failed to displace [H- 3]raclopride from dopamine type 2 binding sites. Unlike haloperidol, B MY 14802, ifenprodil and clozapine, behaviorally effective doses of NP C 16377 did not increase dopamine turnover in the frontal cortex, nucl eus accumbens or corpus striatum of rats. In contrast, each of these a gents increased circulating levels of both adrenocorticotropin and cor ticosterone, but only NPC 16377 decreased circulating plasma levels of prolactin. The results of the current study are consistent with the n otion that NPC 16377 is a potent, selective and orally active sigma si te ligand. At behaviorally relevant doses the compound produces neuroe ndocrine effects both similar to, and different from, neuroleptics, ot her sigma-ligands and atypical antipsychotics, while having no effect on dopamine turnover. Given these data, NPC 16377 should prove to be a useful compound to explore further the physiological and functional s ignificance of sigma-sites in brain.