Emmerson Paul J, McKinzie Jamie H, Surface Peggy L, Suter Todd M, Mitch Charles H, Statnick Michael A
Endocrine Research, Lilly Research Laboratories, Lilly Corporate Center DC0403, Indianapolis, IN 46285, USA.
Eur J Pharmacol. 2004 Jun 28;494(2-3):121-30. doi: 10.1016/j.ejphar.2004.04.050.
Differences in the anorectic activity of morphinan (e.g., naltrexone) and 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4PP) opioid receptor antagonists have been described. In an attempt to explain these differences, the influence of Na(+) on opioid binding affinity and functional activity of 4PP antagonists was compared to other opioid antagonists. The binding affinities of neutral antagonists were unaffected by the addition of Na(+), whereas that for the peptide, inverse agonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI174864) was increased. Similarly, the binding affinities of the 4PP antagonist (3R,4R)-1-((S)-3-hydroxy-3-cyclohexylpropyl)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidine (LY255582) and other 4PP antagonists were increased in the presence of Na(+) with the greatest effects at the delta opioid receptor followed by the mu and kappa opioid receptors, respectively. Similar to ICI174864, 4PP antagonists were found to inhibit basal GTPgamma[(35)S] binding at the delta opioid receptor indicating inverse agonist activity. A correlation was observed between the binding affinities in the presence of Na(+), the inverse agonist potency, and the anorectic potency of 4PP antagonists. These data suggest that 4PP antagonists differ from morphinan antagonists in their inverse agonist activity and suggest a relationship between inverse agonism and anorectic activity.
吗啡喃（如纳曲酮）和3,4 - 二甲基 - 4 -（3 - 羟基苯基）哌啶（4PP）类阿片受体拮抗剂的食欲抑制活性差异已有描述。为了解释这些差异，将Na(+)对4PP拮抗剂阿片结合亲和力和功能活性的影响与其他阿片拮抗剂进行了比较。中性拮抗剂的结合亲和力不受添加Na(+)的影响，而肽类反向激动剂N,N - 二烯丙基 - 酪氨酰 - Aib - Aib - 苯丙氨酰 - 亮氨酸 - 羟基（ICI174864）的结合亲和力增加。同样，在存在Na(+)的情况下，4PP拮抗剂（3R,4R）-1 - [（S）-3 - 羟基 - 3 - 环己基丙基] - 4 -（3 - 羟基苯基）-3,4 - 二甲基 - 1 - 哌啶（LY255582）和其他4PP拮抗剂的结合亲和力增加，对δ阿片受体的影响最大，其次分别是μ和κ阿片受体。与ICI174864类似，发现4PP拮抗剂在δ阿片受体处抑制基础GTPγ[(35)S]结合，表明具有反向激动剂活性。观察到在存在Na(+)时的结合亲和力、反向激动剂效力和4PP拮抗剂的食欲抑制效力之间存在相关性。这些数据表明，4PP拮抗剂在反向激动剂活性方面与吗啡喃拮抗剂不同，并表明反向激动作用与食欲抑制活性之间存在关系。
