title: [Dmt(1)]DALDA analogues with enhanced μ opioid agonist potency and with a mixed μ/κ opioid activity profile.
abstract: Analogues of [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt=2',6'-dimethyltyrosine), a potent μ 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 μ agonist potency, retained μ 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 κ receptor binding affinity and had mixed μ/κ properties. In these cases, molecular dynamics studies indicated conformational preorganization of the unbound peptide ligands due to rotational restriction around the C(β)C(γ) bond of the Xxx(3) residue, in correlation with the observed κ receptor binding enhancement. Compounds with a mixed μ/κ opioid activity profile are known to have therapeutic potential for treatment of cocaine abuse.
authors.affiliation: School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Longxiang
authors.initials: L
authors.lastname: Bai
authors.affiliation: School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Ziyuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada.
authors.forename: Nga N
authors.initials: NN
authors.lastname: Chung
authors.affiliation: Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wilkes
authors.affiliation: School of Pharmacy, Nanjing Medical University, Nanjing 211166, China; Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: l_tingyou@njmu.edu.cn.
authors.forename: Tingyou
authors.initials: T
authors.lastname: Li
authors.affiliation: Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada; Department of Pharmacology, Université de Montréal, Montreal, QC H3C 3J7, Canada. Electronic address: schillp@ircm.qc.ca.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
mesh_terms: D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C424424:2',6'-dimethyltyrosyl-arginyl-phenylalanyl-lysinamide; D009842:Oligopeptides; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu
keywords: Alkylated phenylalanine analogues; Opioid activity profiles; [Dmt(1)]DALDA; μ opioid agonists