Synthesis and in vitro opioid activity profiles of DALDA analogues

The tetrapeptide DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) is a polar and selective m u agonist showing poor penetration of the placental and blood-brain barrier s. In an effort to enhance the potency of DALDA, analogues containing 2',6' -dimethyltyrosine (Dmt), N,2',6'-trimethyltyrosine (Tmt), 2'-methyltyrosine (Mmt) or 2'-hydroxy,6'-methyltyrosine (Hmt) in place of Tyr(1), or Om or a lpha,gamma -diaminobutyric acid (A(2)bu) in place of Lys(4), were synthesiz ed. All compounds displayed high mu receptor selectivity in the rat and gui nea pig brain membrane binding assays and most of them were more potent mu agonists than DALDA in the mu receptor-representative guinea pig ileum assa y, with [Dmt(1)]DALDA showing the highest potency. Because of its extraordi nary mu agonist potency, high mu selectivity, polar character (charge of 3) and metabolic stability, [Dmt(1)]DALDA has potential for use in obstetric al or peripheral analgesia. (C) 2000 Editions scientifiques et medicales El sevier SAS.