Jas Rafal, Bauer Marta, Grodner Błażej, Kończak Weronika, Frączek Karolina, Laskowska Anna K, Milczarek Małgorzata, Kamysz Wojciech, Kleczkowska Patrycja
Maria Sklodowska-Curie Medical Academy in Warsaw, 03-411 Warsaw, Poland.
Department of Analytical Chemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland.
Int J Mol Sci. 2025 May 3;26(9):4356. doi: 10.3390/ijms26094356.
Recently, an old drug, disulfiram, has been shown to reduce cocaine intake by inhibiting dopamine beta (β)-hydroxylase. Its effectiveness was also reported in opioid treatment, as disulfiram attenuated morphine-induced tolerance and dependence. A similar mechanism of action was evident in a selective inhibitor of DβH, nepicastat, particularly in the aspect of cocaine-seeking behavior. Hence, the objective of this study was to verify whether or not nepicastat reproduces disulfiram activity in pain reduction. Moreover, determination of its likely biological effects resulting from interactions with targets other than DβH has been given, in particular acetylcholinesterase. As was found, nepicastat was characterized by the absence of desired antinociceptive activity, though its co-administration with morphine resulted in a dose- and time-dependent enhancement of morphine-induced analgesic effect and attenuation of tolerance. Similarly, nepicastat was found to manifest antimicrobial potency against selected bacterial strains, although the effect was found to be weak. Intriguingly, this compound interacted with acetylcholinesterase through inhibition of its activity. These results clearly indicate nepicastat as a potent molecule that exhibits various biological effects. This, in turn, suggests its possible application in pathological conditions that still require effective treatment.
最近，一种老药双硫仑已被证明可通过抑制多巴胺β（β）-羟化酶来减少可卡因的摄入量。其在阿片类药物治疗中的有效性也有报道，因为双硫仑可减轻吗啡诱导的耐受性和依赖性。在DβH的选择性抑制剂奈匹西他中也明显存在类似的作用机制，特别是在觅可卡因行为方面。因此，本研究的目的是验证奈匹西他是否能重现双硫仑在减轻疼痛方面的活性。此外，还给出了其与DβH以外的靶点相互作用可能产生的生物学效应的测定结果，特别是乙酰胆碱酯酶。结果发现，奈匹西他的特点是没有预期的抗伤害感受活性，尽管它与吗啡联合使用会导致吗啡诱导的镇痛效果呈剂量和时间依赖性增强以及耐受性减弱。同样，发现奈匹西他对选定的细菌菌株具有抗菌效力，尽管效果较弱。有趣的是，该化合物通过抑制乙酰胆碱酯酶的活性与其相互作用。这些结果清楚地表明奈匹西他是一种具有多种生物学效应的有效分子。这反过来又表明它可能应用于仍需要有效治疗的病理状况。
