Karbon E W, Abreu M E, Erickson R H, Kaiser C, Natalie K J, Clissold D B, Borosky S, Bailey M, Martin L A, Pontecorvo M J
Nova Pharmaceutical Corporation, Baltimore, Maryland 21224.
J Pharmacol Exp Ther. 1993 May;265(2):866-75.
6-[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCI (NPC 16377), a structurally novel compound, was found to be a highly potent and selective ligand for sigma-sites. Although 5-fold less potent than haloperidol and 2-fold less potent than ifenprodil to inhibit 1,3-di-o-tolylguanidine binding, NPC 16377 (IC50 = 36 nM) was more potent than alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl butanol (BMY 14802), rimcazole and the atypical antipsychotic, clozapine. A similar rank order of potency was observed when 3H-3-(3-hydroxyphenyl)-N-(1-propyl)piperdine was used as the radioligand. Like BMY, rimcazole and clozapine, NPC 16377 (IC50 = 2671 nM) had low affinity for dopamine type 2 receptors. Additionally, the compound was only weakly active in 35 additional receptor binding assays including those for serotonin2 and serotonin1C receptors. In vivo, NPC 16377 potently inhibited the binding of [3H]-(+)-N-allylnormetazocine to sigma sites after both intraperitoneal and oral administration. At doses 30-fold in excess of the ID50 to inhibit 3HN-allylnormetazocine, NPC 16377 failed to displace [3H]raclopride from dopamine type 2 binding sites. Unlike haloperidol, BMY 14802, ifenprodil and clozapine, behaviorally effective doses of NPC 16377 did not increase dopamine turnover in the frontal cortex, nucleus accumbens or corpus striatum of rats. In contrast, each of these agents increased circulating levels of both adrenocorticotropin and corticosterone, but only NPC 16377 decreased circulating plasma levels of prolactin. The results of the current study are consistent with the notion that NPC 16377 is a potent, selective and orally active sigma site ligand. At behaviorally relevant doses the compound produces neuroendocrine effects both similar to, and different from, neuroleptics, other 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 significance of sigma-sites in brain.
6-[6-(4-羟基哌啶基)己氧基]-3-甲基黄酮盐酸盐（NPC 16377）是一种结构新颖的化合物，被发现是一种高效且选择性的σ位点配体。尽管在抑制1,3-二邻甲苯基胍结合方面，其效力比氟哌啶醇低5倍，比艾芬地尔低2倍，但NPC 16377（IC50 = 36 nM）比α-(4-氟苯基)-4-(5-氟-2-嘧啶基)-1-哌嗪丁醇（BMY 14802）、瑞马唑仑和非典型抗精神病药物氯氮平更有效。当使用3H-3-(3-羟基苯基)-N-(1-丙基)哌啶作为放射性配体时，观察到了类似的效力排序。与BMY、瑞马唑仑和氯氮平一样，NPC 16377（IC50 = 2671 nM）对多巴胺2型受体的亲和力较低。此外，该化合物在另外35种受体结合试验中活性较弱，包括对5-羟色胺2和5-羟色胺1C受体的试验。在体内，腹腔注射和口服后，NPC 16377均能有效抑制[3H]-(+)-N-烯丙基去甲唑嗪与σ位点的结合。在剂量超过抑制3HN-烯丙基去甲唑嗪ID50的30倍时，NPC 16377未能从多巴胺2型结合位点取代[3H]雷氯必利。与氟哌啶醇、BMY 14802、艾芬地尔和氯氮平不同，NPC 16377的行为有效剂量并未增加大鼠额叶皮质、伏隔核或纹状体中的多巴胺周转率。相反，这些药物中的每一种都增加了促肾上腺皮质激素和皮质酮的循环水平，但只有NPC 16377降低了催乳素的循环血浆水平。当前研究结果与以下观点一致，即NPC 16377是一种高效、选择性且口服活性的σ位点配体。在行为相关剂量下，该化合物产生的神经内分泌效应与抗精神病药物、其他σ配体和非典型抗精神病药物既有相似之处，也有不同之处，同时对多巴胺周转率没有影响。鉴于这些数据，NPC 16377应被证明是一种有用的化合物，可进一步探索大脑中σ位点的生理和功能意义。
