Levine A S, Grace M, Billington C J, Zimmerman D M
VA Medical Center Research Service-151, University of Minnesota, Minneapolis 55417.
Brain Res. 1991 Dec 6;566(1-2):193-7. doi: 10.1016/0006-8993(91)91698-z.
A variety of opioid antagonists have been reported to decrease short-term food intake, but few appear to reduce long-term intake. In the present study we evaluated the effect of a relatively new class of opioid antagonists, 3,4-dimethyl-4-phenylpiperidines, on short-term and long-term food intake after central administration. We also evaluated their affinities for the mu and kappa opioid receptor sites in synaptosomal membranes derived from rat whole brain tissue (minus cerebellum) and guinea-pig cortex, respectively. The affinities for the mu receptor sites were LY255582 greater than LY217273 greater than LY256897 greater than naloxone greater than LY227444. The affinities for the kappa receptor sites were LY255582 greater than LY256897 = LY217273 greater than LY227444. LY255582 reduced food intake for up to 24 h after a single intraventricular injection. Doses as low as 1 microgram of LY255582 decreased food intake for up to 4 h. All other drugs were much less powerful. Naloxone and LY256897 only decreased food intake after injection of the 100 microgram dose. LY227444 and LY217273 failed to decrease intake at all doses tested. LY255582 (100 micrograms) decreased food intake over a 7 day period when injected intraventricularly once per day. The body weight of the rats also decreased during the 7 day period. Upon cessation of drug administration body weights and food intake approached control levels. Thus, LY255582 appears to be a very potent and long-acting anorectic agent which may be useful in the treatment of obesity. The mu and kappa binding profile of the phenylpiperidines does not seem to clearly correlate with their anorectic activity.
据报道，多种阿片类拮抗剂可减少短期食物摄入量，但似乎很少能降低长期摄入量。在本研究中，我们评估了一类相对较新的阿片类拮抗剂3,4-二甲基-4-苯基哌啶对中枢给药后短期和长期食物摄入量的影响。我们还分别评估了它们对源自大鼠全脑组织（不含小脑）和豚鼠皮质的突触体膜中μ和κ阿片受体位点的亲和力。对μ受体位点的亲和力为LY255582大于LY217273大于LY256897大于纳洛酮大于LY227444。对κ受体位点的亲和力为LY255582大于LY256897 = LY217273大于LY227444。单次脑室内注射后，LY255582可使食物摄入量减少长达24小时。低至1微克的LY255582剂量可使食物摄入量减少长达4小时。所有其他药物的作用则弱得多。仅在注射100微克剂量后，纳洛酮和LY256897才会减少食物摄入量。在所有测试剂量下，LY227444和LY217273均未能减少摄入量。每天脑室内注射一次LY255582（100微克），可在7天内减少食物摄入量。在此7天期间，大鼠体重也有所下降。停止给药后，体重和食物摄入量接近对照水平。因此，LY255582似乎是一种非常强效且长效的食欲抑制剂，可能对治疗肥胖症有用。苯基哌啶的μ和κ结合特征似乎与其食欲抑制活性没有明显关联。
