France C P, Winger G, Seggel M R, Rice K C, Woods J H
Department of Pharmacology and Experimental Therapeutics, Louisiana State University, New Orleans 70119.
Psychopharmacology (Berl). 1992;109(3):291-8. doi: 10.1007/BF02245876.
The recent synthesis of fentanyl derivatives, some of which appear to have novel profiles of pharmacological effects, has provided compelling evidence that mu opioid efficacy might be altered systematically by modifications in the parent compound fentanyl. In the present study a new 4-(heteroanilido)-piperidine, compound 28, was studied for its effects in rhesus monkeys. In self-administration studies compound 28 maintained rates of lever pressing similar to those maintained by alfentanil; the reinforcing effects of compound 28 were attenuated by the opioid antagonist quadazocine. In drug discrimination studies compound 28 did not substitute for the kappa agonist ethylketocyclazocine and did substitute for the mu agonist alfentanil. In morphine-treated subjects discriminating between saline and naltrexone, compound 28 did not substitute for naltrexone; however, in morphine-abstinent subjects compound 28 reversed naltrexone lever responding. Moreover, this discriminative stimulus effect in morphine-abstinent subjects was antagonized by naltrexone and by quadazocine in a manner consistent with mu receptor mediation. Compound 28 also was an effective analgesic in a warm-water, tail-withdrawal procedure and it decreased markedly respiratory function. The analgesic effects as well as the respiratory depressant effects of compound 28 were antagonized by quadazocine. Together, these results show compound 28 to be a potent, efficacious mu agonist of similar potency to alfentanil. Large differences in apparent efficacy at mu receptors between compound 28 and another compound in this series (mirfentanil), clearly demonstrate that, within this chemical family, small chemical changes can confer significant differences in pharmacologic effect.
最近合成的芬太尼衍生物，其中一些似乎具有新颖的药理作用特征，这提供了令人信服的证据，表明通过对母体化合物芬太尼进行修饰，μ阿片样物质的效力可能会被系统性改变。在本研究中，对一种新的4-（杂芳基氨基）-哌啶化合物28在恒河猴身上的作用进行了研究。在自我给药研究中，化合物28维持的杠杆按压速率与阿芬太尼维持的速率相似；化合物28的强化作用被阿片样物质拮抗剂夸达佐辛减弱。在药物辨别研究中，化合物28不能替代κ激动剂乙基酮环唑辛，但能替代μ激动剂阿芬太尼。在区分盐水和纳曲酮的吗啡处理受试者中，化合物28不能替代纳曲酮；然而，在吗啡戒断的受试者中，化合物28逆转了纳曲酮的杠杆反应。此外，在吗啡戒断的受试者中，这种辨别性刺激作用以与μ受体介导一致的方式被纳曲酮和夸达佐辛拮抗。化合物28在温水甩尾试验中也是一种有效的镇痛药，并且它显著降低了呼吸功能。化合物28的镇痛作用以及呼吸抑制作用被夸达佐辛拮抗。总之，这些结果表明化合物28是一种与阿芬太尼效力相似的强效、有效的μ激动剂。该系列中的化合物28与另一种化合物（米芬太尼）在μ受体上的表观效力存在很大差异，这清楚地表明，在这个化学家族中，微小的化学变化可导致药理作用的显著差异。
