Taylor D P, Eison M S, Moon S L, Schlemmer R F, Shukla U A, VanderMaelen C P, Yocca F D, Gallant D J, Behling S H, Boissard C G
CNS Biology, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Wallingford, CT 06492-7660.
NIDA Res Monogr. 1993;133:125-57.
BMY 14802 was identified as a potential antipsychotic drug in traditional model systems, and this identification was confirmed in modern behavioral and electrophysiological systems. The drug appears to be atypical as an antipsychotic in its lack of activity in models predictive of the potential to produce extrapyramidal side effects and tardive dyskinesia. Indeed, this suggestion is corroborated by clinical findings to date. The atypical profile of BMY 14802 extends to its neurochemical actions and appears to find its basis in regionally selective, indirect modulation of the dopamine system. Furthermore, BMY 14802 exhibits interactions with sigma binding sites in vitro and in vivo, a notion supported by data from neurophysiological, behavioral, and biochemical investigations. BMY 14802 also appears to be neuroprotective in some model systems and may have utility in the treatment of stroke (Boissard et al. 1991). BMY 14802 appears to interact with 5-HT1A receptors, but this interaction does not seem to contribute significantly to the potential antipsychotic actions of the drug. Moreover, the formation of active metabolites of BMY 14802 does not appear to occur in animals or humans to an extent of physiological or behavioral relevance. If clinically efficacious, BMY 14802 may treat the symptoms of schizophrenia by a mechanism novel for antipsychotic drugs: regionally selective, indirect modulation of dopaminergic systems by specific interaction at sigma sites.
BMY 14802在传统模型系统中被鉴定为一种潜在的抗精神病药物,并且这一鉴定在现代行为和电生理系统中得到了证实。作为一种抗精神病药物,该药物似乎是非典型的,因为它在预测产生锥体外系副作用和迟发性运动障碍可能性的模型中缺乏活性。事实上,迄今为止的临床研究结果证实了这一推测。BMY 14802的非典型特征扩展到其神经化学作用,并且似乎基于对多巴胺系统的区域选择性间接调节。此外,BMY 14802在体外和体内均表现出与σ结合位点的相互作用,神经生理学、行为学和生物化学研究的数据支持了这一观点。BMY 14802在某些模型系统中似乎还具有神经保护作用,可能对中风治疗有用(布瓦萨尔等人,1991年)。BMY 14802似乎与5-HT1A受体相互作用,但这种相互作用似乎对该药物的潜在抗精神病作用没有显著贡献。此外,BMY 14802的活性代谢产物在动物或人类中的形成似乎未达到具有生理或行为相关性的程度。如果在临床上有效,BMY 14802可能通过一种抗精神病药物的新机制来治疗精神分裂症症状:通过在σ位点的特异性相互作用对多巴胺能系统进行区域选择性间接调节。