title: Rational design of dynorphin A analogues with delta-receptor selectivity and antagonism for delta- and kappa-receptors.
abstract: Substitution of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in place of Gly2 in dynorphin A-(1-13)-NH2 and -(1-11)-NH2 (DYN) analogues (1 and 2) decreased the affinity to the kappa, delta, and mu receptors, and kappa selectivity. The analogue [D-Ala2, des-Gly3]DYN (4), a chimera between deltorphin/dermorphin N-terminal tripeptide and DYN, was virtually inactive for kappa-sites while the affinities for delta- and mu-receptors remained essentially unchanged. The doubly substituted analogue [2',6'-dimethyl-L-tyrosine (Dmt1)-Tic2]DYN (3) exhibited high delta-affinity (Ki=0.39 nM) while mu- and kappa-affinities were only an order of magnitude less (4-5 nM). Bioactivity of [Tic2]DYN peptides (1-3) on guinea-pig ileum and rabbit jejunum revealed potent delta- and kappa-antagonism, while the delta agonist potency of 4 was comparable to DYN. Thus, conversion from a kappa-agonist to antagonist occurred with the inclusion of Tic into DYN analogues, similar to the appearance of antagonist properties with delta- and mu-opioid agonists containing a Tic2 residue.
authors.affiliation: Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: A
authors.initials: A
authors.lastname: Capasso
authors.forename: M
authors.initials: M
authors.lastname: Marastoni
authors.forename: S D
authors.initials: SD
authors.lastname: Bryant
authors.forename: P S
authors.initials: PS
authors.lastname: Cooper
authors.forename: L H
authors.initials: LH
authors.lastname: Lazarus
authors.forename: P A
authors.initials: PA
authors.lastname: Temussi
authors.forename: S
authors.initials: S
authors.lastname: Salvadori
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004399:Dynorphins / Q000138:chemical synthesis / Q000494:pharmacology*; D004594:Electrophysiology; D006168:Guinea Pigs; D007082:Ileum; D007546:Isoquinolines / Q000737:chemistry; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009842:Oligopeptides / Q000737:chemistry; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D011817:Rabbits; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines
chemical_list: D000701:Analgesics, Opioid; D007546:Isoquinolines; D009842:Oligopeptides; D010446:Peptide Fragments; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; C111616:dynorphin A (1-11)-amide; C111618:dynorphin A, Ala(2)-des-Gly(3)-; C111617:dynorphin A, Dmt(1)-Tic(2)-; C059567:deltorphin; C078986:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; C026843:dynorphin (1-13); D004399:Dynorphins