Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 35, Issue 10, Pages 895-901Publisher
EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/S0223-5234(00)01171-5
Keywords
mu opioid agonists; DALDA; DALDA analogues; [Dmt(1)]DALDA; opioid receptor binding assays; GPI and MVD bioassays; opoid peptides
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Funding
- NIDA NIH HHS [P01-DA08924] Funding Source: Medline
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The tetrapeptide DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) is a polar and selective mu agonist showing poor penetration of the placental and blood-brain barriers. 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 alpha,gamma -diaminobutyric acid (A(2)bu) in place of Lys(4), were synthesized. All compounds displayed high mu receptor selectivity in the rat and guinea pig brain membrane binding assays and most of them were more potent mu agonists than DALDA in the mu receptor-representative guinea pig ileum assay, with [Dmt(1)]DALDA showing the highest potency. Because of its extraordinary mu agonist potency, high mu selectivity, polar character (charge of 3+) and metabolic stability, [Dmt(1)]DALDA has potential for use in obstetrical or peripheral analgesia. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
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