Hoffman A J, Nichols D E
J Med Chem. 1985 Sep;28(9):1252-5. doi: 10.1021/jm00147a022.
A convenient method for the synthesis of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives was developed. A series of these compounds was synthesized and tested for substitution in the two-lever drug discrimination assay, in rats trained to discriminate injections of d-LSD tartrate (185.5 nmol/kg, ip) from saline. A dose-response curve for each of the compounds in the series was generated. Structure-activity relationships were developed, based on comparison of the estimated ED50 values from these curves. Of the compounds that substituted for LSD, the N(6)-ethyl and -allyl were approximately 2-3 times more potent than LSD itself. The N(6)-propyl was equipotent to LSD, while the isopropyl derivative was half as active. The n-butyl compound was 1 order of magnitude less potent than LSD, suggesting a similarity to the SAR of certain serotonin and dopamine agonists. By contrast, no generalization occurred to norlysergic acid N,N-diethylamide and the N(6)-2-phenethyl derivative.
开发了一种合成N(6)-烷基去甲麦角酸N,N-二乙酰胺衍生物的简便方法。合成了一系列这些化合物，并在经过训练以区分注射d-酒石酸麦角酰二乙胺（185.5 nmol/kg，腹腔注射）和生理盐水的大鼠中进行双杠杆药物辨别试验，以测试其替代作用。生成了该系列中每种化合物的剂量-反应曲线。基于对这些曲线估计的ED50值的比较，建立了构效关系。在替代麦角酰二乙胺的化合物中，N(6)-乙基和-烯丙基的效力约为麦角酰二乙胺本身的2-3倍。N(6)-丙基与麦角酰二乙胺效力相当，而异丙基衍生物的活性只有其一半。正丁基化合物的效力比麦角酰二乙胺低1个数量级，这表明其与某些血清素和多巴胺激动剂的构效关系相似。相比之下，去甲麦角酸N,N-二乙酰胺和N(6)-2-苯乙基衍生物没有出现这种普遍规律。
