Katsura Y, Zhang X, Homma K, Rice K C, Calderon S N, Rothman R B, Yamamura H I, Davis P, Flippen-Anderson J L, Xu H, Becketts K, Foltz E J, Porreca F
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Med Chem. 1997 Aug 29;40(18):2936-47. doi: 10.1021/jm970106d.
A series of N-alkyl- and N,N-dialkyl-4-[alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl] benzyl]-benzamides were synthesized and evaluated for binding affinities at mu, delta, and kappa opioid receptor subtypes. Several compounds (2e,f,h,i,m) strongly bound to the delta receptor with IC50 values in the nanomolar range. On the other hand, the binding affinities of these compounds for the mu and kappa receptors were in the micromolar or greater range indicating excellent delta opioid receptor subtype selectivities. In this series, two important structure-activity relationships were found for the delta receptor binding affinity. First, the spatial orientation of the alpha-benzylic position influenced the affinities with the alpha R derivatives 2a-n generally showing more than 10-fold greater affinity than the alpha S derivatives 3a-n. Second, the binding affinities were strongly influenced by the number of alkyl substituents on the amide nitrogen. N-Monoalkylbenzamide derivatives 2b-d showed lower affinity than N,N-dialkylbenzamide derivatives 2e-n, and the N-unsubstituted benzamide derivative 2a had the lowest affinity for the delta receptor in the series. The dramatic effect of the amide group substitution pattern on the binding affinity for the delta receptor strongly suggests that the amide function is an important structural element in the interaction of this series of compounds at the delta receptor. Selective compounds in this series were examined for binding affinity in cloned human mu and delta receptors. The results obtained generally paralleled those from the rat brain binding assay. Compounds 2e,f with potent delta binding affinities and high delta selectivities were shown to be delta agonists with high selectivity by studies in the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Compound 2f was the most selective compound in the rat brain and GPI/MVD assays with 1755- and 958-fold delta vs mu selectivity, respectively.
合成了一系列N-烷基和N,N-二烷基-4-[α-[(2S,5R)-4-烯丙基-2,5-二甲基-1-哌嗪基]苄基]-苯甲酰胺，并对其在μ、δ和κ阿片受体亚型上的结合亲和力进行了评估。几种化合物（2e、f、h、i、m）与δ受体强烈结合，IC50值在纳摩尔范围内。另一方面，这些化合物对μ和κ受体的结合亲和力在微摩尔或更高范围内，表明具有优异的δ阿片受体亚型选择性。在该系列中，发现了与δ受体结合亲和力相关的两个重要构效关系。首先，α-苄基位置的空间取向影响亲和力，α-R衍生物2a-n的亲和力通常比α-S衍生物3a-n高10倍以上。其次，结合亲和力受酰胺氮上烷基取代基数量的强烈影响。N-单烷基苯甲酰胺衍生物2b-d的亲和力低于N,N-二烷基苯甲酰胺衍生物2e-n，且N-未取代的苯甲酰胺衍生物2a在该系列中对δ受体的亲和力最低。酰胺基团取代模式对δ受体结合亲和力的显著影响强烈表明，酰胺功能是该系列化合物与δ受体相互作用中的一个重要结构要素。对该系列中的选择性化合物在克隆的人μ和δ受体中进行了结合亲和力检测。获得的结果总体上与大鼠脑结合试验的结果相似。通过在豚鼠回肠（GPI）和小鼠输精管（MVD）制剂中的研究表明，具有强δ结合亲和力和高δ选择性的化合物2e、f是具有高选择性的δ激动剂。化合物2f是大鼠脑和GPI/MVD试验中最具选择性的化合物，δ对μ的选择性分别为1755倍和958倍。
