Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist.
Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist.
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发表时间：
2001-05
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通讯作者：
Peng Huang;George B Kehner;Alan Cowan;L. Liu-Chen
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作者：
Peng Huang;George B Kehner;Alan Cowan;L. Liu-Chen
丁丙诺啡（BUP）是一种有益于阿片类药物依赖个体维持治疗的奥巴平镇痛药。尽管BUP已被广泛研究，但对BUP的主要脱烷基代谢物去丁丙诺啡（norBUP）知之甚少。我们现在描述了norBUP与阿片样物质和伤害肽/孤啡肽FQ （ORL1）受体的结合，以及它对阿片样物质或ORL1受体介导的[(35)S]鸟苷-5'- o -（γ -硫）三磷酸（[(35)S]GTP γ S）结合的影响和小鼠醋酸扭体试验。用稳定转染各受体的中国仓鼠卵巢细胞进行受体结合和[(35)S]GTP γ S结合。NorBUP对K(i)值在纳摩尔或亚纳摩尔范围内的mu-、delta-和kappa-阿片受体表现出高亲和力，与BUP相当。NorBUP和BUP对ORL1受体的亲和力较低，K(i)值在微摩尔范围内。在[(35)S]GTP γ S结合试验中，norBUP表现出与BUP不同的特征。在δ受体上，norBUP是一种有效的完全激动剂，但BUP没有激动剂活性，并具有norBUP和DPDPE的拮抗作用。在mu-和kappa-受体上，norBUP和BUP都是有效的部分激动剂，其中norBUP有中等疗效，而BUP有低疗效。在ORL1受体上，norBUP是低效的完全激动剂，而BUP是强效的部分激动剂。在扭体实验中，BUP和norBUP均有效且呈剂量依赖性地抑制扭体，A（50）值分别为0.067和0.21 mg/kg, s.c。这些结果突出了BUP和norBUP之间的异同，每一个都可能影响BUP独特的药理学特征。
Buprenorphine (BUP) is an oripavine analgesic that is beneficial in the maintenance treatment of opiate-dependent individuals. Although BUP has been studied extensively, relatively little is known about norbuprenorphine (norBUP), a major dealkylated metabolite of BUP. We now describe the binding of norBUP to opioid and nociceptin/orphanin FQ (ORL1) receptors, and its effects on [(35)S]guanosine-5'-O-(gamma-thio)triphosphate ([(35)S]GTP gamma S) binding mediated by opioid or ORL1 receptors and in the mouse acetic acid writhing test. Chinese hamster ovary cells stably transfected with each receptor were used for receptor binding and [(35)S]GTP gamma S binding. NorBUP exhibited high affinities for mu-, delta-, and kappa-opioid receptors with K(i) values in the nanomolar or subnanomolar range, comparable to those of BUP. NorBUP and BUP had low affinities for the ORL1 receptor with K(i) values in the micromolar range. In the [(35)S]GTP gamma S binding assay, norBUP displayed characteristics distinct from BUP. At the delta-receptor, norBUP was a potent full agonist, yet BUP had no agonist activity and antagonized actions of norBUP and DPDPE. At mu- and kappa-receptors, both norBUP and BUP were potent partial agonists, with norBUP having moderate efficacy and BUP having low efficacy. At the ORL1 receptor, norBUP was a full agonist with low potency, while BUP was a potent partial agonist. In the writhing test, BUP and norBUP both suppressed writhing in an efficacious and dose-dependent manner, giving A(50) values of 0.067 and 0.21 mg/kg, s.c., respectively. These results highlight the similarities and differences between BUP and norBUP, each of which may influence the unique pharmacological profile of BUP.