对δ阿片受体具有更高亲和力和选择性的[D-青霉胺2，D-青霉胺5]脑啡肽类似物。

[D-Pen2,D-Pen5]enkephalin analogues with increased affinity and selectivity for delta opioid receptors.

作者信息

Toth G, Kramer T H, Knapp R, Lui G, Davis P, Burks T F, Yamamura H I, Hruby V J

机构信息

Department of Chemistry, University of Arizona, Tucson 85721.

出版信息

J Med Chem. 1990 Jan;33(1):249-53. doi: 10.1021/jm00163a041.

DOI:10.1021/jm00163a041

PMID:2153205

Abstract

The conformationally restricted, cyclic disulfide-containing enkephalin analogue [D-Pen2,D-Pen5]enkephalin (DPDPE) was modified by halogenation (F, Cl, Br, I) of the phenylalanine-4 residue in the para position. The potency and selectivity of these analogues for the delta opioid receptor was greater than that of the parent peptide. The analogues possessed greater potency and affinity for the delta receptors than DPDPE in the mouse vas deferens assay and in radioreceptor assays (against [3H]DPDPE), respectively. [p-ClPhe4]DPDPE was the most selective in the radioligand binding assays (IC50(mu)/IC50(delta) = 574), being about 5-fold more delta opioid receptor selective than DPDPE in this assay, whereas [p-IPhe4]DPDPE was the most selective in the classical bioassay systems using the mouse vas deferens and guinea pig ileum assays (IC50(GPI)/IC50(MVD) = 17,374), making it nearly 9-fold more selective than DPDPE in direct comparisons using the same assay conditions.

摘要

构象受限的含环二硫键脑啡肽类似物[D-青霉胺2，D-青霉胺5]脑啡肽（DPDPE）通过对4位苯丙氨酸残基的对位进行卤化（氟、氯、溴、碘）修饰。这些类似物对δ阿片受体的效力和选择性高于母体肽。在小鼠输精管试验和放射受体试验（针对[3H]DPDPE）中，这些类似物分别对δ受体具有比DPDPE更高的效力和亲和力。[对氯苯丙氨酸4]DPDPE在放射性配体结合试验中选择性最高（IC50（μ）/IC50（δ） = 574），在此试验中对δ阿片受体的选择性比DPDPE高约5倍，而[对碘苯丙氨酸4]DPDPE在使用小鼠输精管和豚鼠回肠试验的经典生物测定系统中选择性最高（IC50（GPI）/IC50（MVD） = 17,374），在相同试验条件下直接比较时，其选择性比DPDPE高近9倍。