Novel µ opioid antagonists derived from the µ opioid agonists endomorphin and [Dmt1]DALDA (H‐Dmt‐D‐Arg‐Phe‐Lys‐NH2). (2nd August 2020)

• Record Type: Journal Article
• Authors: Shi, Saijian; Xu, Jian; Feng, LingLing; Fan, Xin; Chen, Zhen; Qin, Yajuan; Chung, Nga N.; Li, Tingyou; Schiller, Peter W.
• Is Part Of: Chemical biology & drug design. Volume 96:Number 5(2020)
• Page Start: 1305
• Page End: 1314
• Publication Date: 2020-08-02
• Subjects: [Dmt1]DALDA -- endomorphin -- mu opioid receptor antagonists -- opioid activity profiles -- proline analogues; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13743
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: Hybrid analogues of the µ opioid agonists endomorphin and [Dmt 1 ]DALDA (H‐Dmt‐D‐Arg‐Phe‐Lys‐NH2, Dmt = 2′, 6′‐dimethyltyrosine) containing cis ‐4‐amino‐Pro, trans ‐4‐amino‐Pro, cis ‐4‐aminoethyl‐Pro or cis ‐4‐guanidinylethyl‐Pro in the 2 position of the peptide sequence were synthesized. None of the compounds retained high µ opioid agonist activity and, unexpectedly, substitution of cis ‐4‐amino‐Pro resulted in a novel class of potent µ opioid antagonists. In particular, the compound H‐Dmt‐ cis ‐4‐amino‐Pro‐Trp‐Lys‐NH2 (CZ‐1) turned out to be a highly selective µ opioid antagonist with ~1 nM µ receptor binding affinity. Abstract : Replacement of the D‐Arg residue in µ opioid agonist peptide analogues of [Dmt1]DALDA (Dmt = 2′, 6′‐dimethyltyrosine) with cis‐4‐amino‐Pro resulted in selective µ opioid antagonists with low nanomolar µ opioid receptor binding affinity.