Ghirmai Senait, Azar Marc R, Cashman John R
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA.
Bioorg Med Chem. 2009 Sep 15;17(18):6671-81. doi: 10.1016/j.bmc.2009.07.069. Epub 2009 Aug 6.
A series of substituted aryl amide derivatives of 6-naltrexamine, 3 designed to be metabolically stable were synthesized and used to characterize the structural requirements for their potency to binding and functional activity of human mu (mu), delta (delta) and kappa (kappa) opioid and nociceptin (NOP) receptors. Binding assays showed that 4-10 had subnanomolar K(i) values for mu and kappa opioid receptors. Functional assays for stimulation of [(35)S]GTPgammaS binding showed that several compounds acted as partial or inverse agonists and antagonists of the mu and delta, kappa opioid or NOP receptors. The compounds showed considerable stability in the presence of rat, mouse or human liver preparations and NADPH. The inhibitory activity on the functional activity of human cytochrome P450s was examined to determine any potential inhibition by 4-9. Only modest inhibition of CYP3A4, CYP2C9 and CYP2C19 was observed for a few of the analogs. As a representative example, radiolabeled 6 was examined in vivo and showed reasonable brain penetration. The inhibition of ethanol self-administration in rats trained to self-administer a 10% (w/v) ethanol solution, utilizing operant techniques showed 5-8 to have very potent efficacy (ED(50) values 19-50 microg/kg).
合成了一系列旨在具有代谢稳定性的6-纳曲胺的取代芳基酰胺衍生物3，并用于表征它们对人μ（mu）、δ（delta）和κ（kappa）阿片受体以及孤啡肽（NOP）受体的结合效力和功能活性的结构要求。结合试验表明，4-10对μ和κ阿片受体的K（i）值低于纳摩尔。刺激[（35）S]GTPγS结合的功能试验表明，几种化合物作为μ和δ、κ阿片受体或NOP受体的部分激动剂、反向激动剂和拮抗剂起作用。这些化合物在大鼠、小鼠或人肝脏制剂和NADPH存在下表现出相当的稳定性。检测了它们对人细胞色素P450功能活性的抑制活性，以确定4-9是否有任何潜在抑制作用。仅观察到少数类似物对CYP3A4、CYP2C9和CYP2C19有适度抑制。作为一个代表性例子，对放射性标记的6进行了体内检测，结果显示其具有合理的脑渗透性。利用操作性技术，对训练自行给予10%（w/v）乙醇溶液的大鼠进行乙醇自我给药抑制试验，结果显示5-8具有非常强的效力（ED（50）值为19-50μg/kg）。
