Gottschlich R, Barber A, Bartoszyk G D, Seyfried C A
E. Merck, Preclinical Pharmaceutical Research, Darmstadt, Germany.
Drugs Exp Clin Res. 1995;21(5):171-4.
EMD 61753 (N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl) -ethyl ]- 2,2-diphenyl-acetamide hydrochloride) is a peripherally selective kappa-opiate agonist. It exhibits antihyperalgesic activity in animal models of inflammatory pain at doses which do not cause signs of central action. The structure of this compound was varied in different ways and the resulting derivatives were tested for affinity to the kappa-receptor. Furthermore, those compounds with binding values comparable to that of EMD 61753 were tested for central activity. This was done by measuring the extent to which the haloperidol-induced L-DOPA accumulation in the nucleus accumbens of the rat could be reversed after application of 10 mg/kg s.c. of the test compound. Structure-activity relationships revealed that none of the analogues or reference compounds tested is superior to the parent compound with regard to its favourable ratio between kappa-receptor affinity and peripheral selectivity.
EMD 61753（N-甲基-N-[(1S)-1-苯基-2-((3S)-3-羟基吡咯烷-1-基)-乙基]-2,2-二苯基乙酰胺盐酸盐）是一种外周选择性κ-阿片受体激动剂。在不引起中枢作用迹象的剂量下，它在炎症性疼痛的动物模型中表现出抗痛觉过敏活性。该化合物的结构以不同方式进行了改变，并对所得衍生物进行了κ-受体亲和力测试。此外，对那些结合值与EMD 61753相当的化合物进行了中枢活性测试。这是通过测量在皮下注射10 mg/kg测试化合物后，大鼠伏隔核中氟哌啶醇诱导的L-多巴积累的逆转程度来完成的。构效关系表明，在所测试的类似物或参考化合物中，没有一种在κ-受体亲和力和外周选择性之间的有利比率方面优于母体化合物。
