[Dmt1] DALDA analogues with enhanced μ opioid agonist potency and with a mixed μ/κ opioid activity profile

Analogues of [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2; Dmt = 2',6'-dimethyltyrosine), a potent mu opioid agonist peptide with mitochondria-targeted antioxidant activity, were prepared by replacing Phe(3) with various 2',6'-dialkylated Phe analogues, including 2',6'-dimethylphenylalanine (Dmp), 2',4',6'-trimethylphenylalanine (Tmp), 2'-isopropyl-6'-methylphenylalanine (Imp) and 2'-ethyl-6'-methylphenylalanine (Emp), or with the bulky amino acids 3'-(1-naphthyl)alanine (1-Nal), 3'-(2-naphthyl)alanine (2-Nal) or Trp. Several compounds showed significantly increased mu agonist potency, retained mu receptor selectivity and are of interest as drug candidates for neuropathic pain treatment. Surprisingly, the Dmp(3)-, Imp(3)-, Emp(3)- and 1-Nal(3)-containing analogues showed much increased kappa receptor binding affinity and had mixed mu/kappa properties. In these cases, molecular dynamics studies indicated conformational preorganization of the unbound peptide ligands due to rotational restriction around the C-beta-C-gamma bond of the Xxx(3) residue, in correlation with the observed kappa receptor binding enhancement. Compounds with a mixed mu/kappa opioid activity profile are known to have therapeutic potential for treatment of cocaine abuse. (c) 2014 Elsevier Ltd. All rights reserved.