Rothman R B, Xu H, Char G U, Kim A, De Costa B R, Rice K C, Zimmerman D M
Clinical Psychopharmacology Section, NIDA Addiction Research Center, Baltimore, MD 21224.
Peptides. 1993 Jan-Feb;14(1):17-20. doi: 10.1016/0196-9781(93)90005-2.
Certain opioid antagonists of the phenylpiperidine series (PPAs), such as LY255582, seem uniquely efficacious at producing weight loss in lean and meal-fed obese Zucker rats. Comparison of the pharmacological and receptor binding profile of PPAs that promote marked weight loss with those that do not has failed to find any obvious differences between these two groups of narcotic antagonists, which might explain the differences in their biological activities. The potent stimulatory effect of dynorphin, and other kappa agonists, on feeding behavior suggests that the antagonists that promote weight loss might have high affinity for kappa receptors. The recent demonstration by several laboratories of kappa receptor heterogeneity prompted us to test the hypothesis that the antagonists that promote weight loss might have high affinity for a subtype of kappa binding sites. In the present study, therefore, we determined the Ki values of five PPAs, naloxone, and naltrexone at mu, delta, kappa 1, kappa 2a, and kappa 2b binding sites. The data indicate that antagonists have subnanomolar Ki values and high selectivity for the kappa 2b binding site (relative to the kappa 2a binding site) are efficacious at promoting weight loss.
某些苯基哌啶系列（PPAs）的阿片类拮抗剂，如LY255582，在使瘦型和进食后的肥胖Zucker大鼠体重减轻方面似乎具有独特的功效。将能显著促进体重减轻的PPAs与不能促进体重减轻的PPAs的药理学和受体结合谱进行比较，未能发现这两组麻醉拮抗剂之间存在任何明显差异，而这些差异或许可以解释它们生物学活性的不同。强啡肽及其他κ激动剂对摄食行为具有强烈的刺激作用，这表明能促进体重减轻的拮抗剂可能对κ受体具有高亲和力。最近多个实验室证实了κ受体的异质性，这促使我们去检验这样一个假设，即能促进体重减轻的拮抗剂可能对κ结合位点的某一亚型具有高亲和力。因此，在本研究中，我们测定了五种PPAs、纳洛酮和纳曲酮在μ、δ、κ1、κ2a和κ2b结合位点的Ki值。数据表明，拮抗剂具有亚纳摩尔级的Ki值，且对κ2b结合位点（相对于κ2a结合位点）具有高选择性，在促进体重减轻方面是有效的。
