(-)-U-50488 hydrochloride is a selective agonist of the kappa opioid receptor (KOR) with an IC50 value of 0.25μM[1]. (-)-U-50488 hydrochloride activates KOR, which has been implicated in physiological processes studied in pain modulation, emotion regulation, and addiction[1]. (-)-U-50488 hydrochloride has been mainly used to study behavioral effects, stress response, and cognitive function in animal models[2].
In vitro, human monocyte-derived macrophages (MDM) cultures were established for HIV-1 infection[3]. (-)-U-50488 hydrochloride (30pg/ml) was added to MDM culture media, and supernatant was harvested on day 7 and day 14 post infection to evaluate the direct effect of KOR activation on HIV-1 expression[3]. Addition of (-)-U-50488 hydrochloride (0.1pM) significantly inhibited HIV-1 expression both at day 7 and day 14 after infection[3]. Pretreatment of 1pM Nor-BNI inhibiting KOR activation decreased the inhibitory effect of (-)-U-50488 hydrochloride (0.1pM) on HIV-1 expression by >65%[3]. Therefore, anti-HIV-1 effect of (-)-U-50488 hydrochloride was regulated by KOR activation[3].
In vivo, adult C57BL/6J mice (6 female and 6 male) were euthanized, and 300μm thick coronal brain sections were prepared to investigate the effects of (-)-U-50488 hydrochloride on dopamine release[4]. 10, 30, 100, 300, 1000nM of (-)-U-50488 hydrochloride were bath applied to sections, and KOR agonist curve responding to dopamine were analyzed[4,5]. Activation of KOR inhibited dopamine release, with no observed sex differences in mice[4]. Moreover, treatment with (-)-U-50488 hydrochloride did not affect dopamine uptake in any of the nucleus accumbens core subregions[4].
References:
[1]Zhao Y, Joshi AA, Aldrich JV, Murray TF. Quantification of kappa opioid receptor ligand potency, efficacy and desensitization using a real-time membrane potential assay. Biomedicine & Pharmacotherapy. 2021 Nov 1;143:112173.
[2]Callaghan CK, Rouine J, Islam MN, Eyerman DJ, Smith KL, Blumberg L, Sanchez C, O’Mara SM. Differential effects of opioid receptor modulators on motivational and stress-coping behaviors in the back-translational rat IFN-α depression model. bioRxiv. 2019 Sep 28:769349.
[3]Chao CC, Gekker G, Sheng WS, Hu S, Peterson PK. U50488 inhibits HIV-1 expression in acutely infected monocyte-derived macrophages. Drug and alcohol dependence. 2001 Apr 1;62(2):149-54.
[4]Karkhanis AN, West AM, Jones SR. Kappa opioid receptor agonist U50, 488 inhibits dopamine more in caudal than rostral nucleus accumbens core. Basic & clinical pharmacology & toxicology. 2023 Nov;133(5):526-34.
[5]Karkhanis AN, Rose JH, Weiner JL, Jones SR. Early-life social isolation stress increases kappa opioid receptor responsiveness and downregulates the dopamine system. Neuropsychopharmacology. 2016 Aug;41(9):2263-74.
(-)-U-50488 hydrochloride（(-)-U-50488盐酸盐）是一种选择性kappa阿片受体（KOR）激动剂，IC50值为 0.25μM[1]。 (-)-U-50488盐酸盐可激活KOR，KOR与疼痛调节、情绪调节和成瘾研究的生理过程有关[1]。 (-)-U-50488盐酸盐主要用于研究动物模型的行为效应、应激反应和认知功能[2]。
在体外，人类单核细胞中的巨噬细胞（MDM）被提取用于建立HIV-1感染模型[3]。将(-)-U-50488盐酸盐（30pg/ml）添加到MDM培养基中，并在感染后第7天和第14天收集上清液，以评估 KOR激活对 HIV-1 表达的直接影响[3]。添加(-)-U-50488盐酸（0.1pM）可在感染后第7天和第14天显着抑制HIV-1表达[3]。抑制KOR激活的1pM Nor-BNI预处理可使(-)-U-50488盐酸盐（0.1pM）对HIV-1表达的抑制作用降低>65%[3]。因此，(-)-U-50488盐酸盐的抗HIV-1作用是通过KOR激活来调节的[3]。
在体内，对成年C57BL/6J小鼠（6只雌性和6只雄性）进行安乐死，并制备300μm厚的冠状脑切片，研究(-)-U-50488盐酸盐对多巴胺释放的影响[4]。将10、30、100、300、1000nM的(-)-U-50488盐酸盐浸浴脑切片，分析KOR激动剂对多巴胺的响应曲线[4,5]。 KOR 的激活抑制多巴胺释放，在小鼠中没有观察到性别差异[4]。此外，(-)-U-50488 盐酸盐治疗不会影响任何伏隔核核心分区的多巴胺摄取[4]。