Wentland Mark P, Lou Rongliang, Lu Qun, Bu Yigong, VanAlstine Melissa A, Cohen Dana J, Bidlack Jean M
Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Bioorg Med Chem Lett. 2009 Jan 1;19(1):203-8. doi: 10.1016/j.bmcl.2008.10.134. Epub 2008 Nov 7.
A series of 15 novel opioid derivatives were made where the prototypic phenolic-OH group of traditional opioids was replaced by a carboxamido (CONH(2)) group. For 2,6-methano-3-benzazocines and morphinans similar or, in a few instances, enhanced affinity for mu, delta and kappa opioid receptors was observed when the OH-->CONH(2) switch was applied. For 4,5alpha-epoxymorphinans, binding affinities for the corresponding carboxamide derivatives were much lower than the OH partner consistent with our pharmacophore hypothesis concerning carboxamide bioactive conformation. The active metabolite of tramadol and its carboxamide counterpart had comparable affinities for the three receptors.
制备了一系列15种新型阿片类衍生物，其中传统阿片类药物的原型酚羟基被羧酰胺（CONH₂）基团取代。对于2,6-亚甲基-3-苯并氮杂卓类和吗啡喃类，当进行OH→CONH₂转换时，观察到对μ、δ和κ阿片受体具有相似的亲和力，在少数情况下亲和力增强。对于4,5α-环氧吗啡喃类，相应羧酰胺衍生物的结合亲和力远低于羟基对应物，这与我们关于羧酰胺生物活性构象的药效团假说一致。曲马多的活性代谢物及其羧酰胺类似物对三种受体具有相当的亲和力。
