title: Comparison with naloxone of two dynorphin A analogues with K- and delta-opioid antagonist activity.
abstract: Recently, we have demonstrated that substitution of 1,2,3,4 tetrahyidroisoquinoline-3- carboxylic acid (Tic) in place of Gly2 in dynorphin A-(1-13)-NH2 (DYN) analogue (A) decreased the affinity to the kappa, delta, and micro receptors, and kappa selectivity. The doubly substituted analogue [2',6'-dimethyl-L-tyrosine (Dmt1)-Tic2]DYN (B) exhibited high delta-affinity (Ki=0.39 nM) while micro- and kappa-affinities were only an order of magnitude less (4-5 nM). Bioactivity of [Tic2]DYN peptide (A) on guinea-pig ileum and rabbit jejunum revealed potent delta- and kappa-antagonism thus indicating that the 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-opioid agonists containing a Tic2 residue. The present study was undertaken to compare the k- and delta-opioid antagonistic activity of two [Tic2] DYN peptides (A and B) with naloxone a well known non selective opioid receptor antagonist. This comparison was performed by using the model of opioid withdrawal in vitro. Following a 4 min in vitro exposure to U50-488 H (10(-8) M), a selective k opioid receptor agonist, the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone (10(-5) M). Also, following a 4 min in vitro exposure to deltorphin II (10(-8) M), a selective delta opioid receptor agonist, the rabbit jejunum exhibited a strong contracture after the addition of naloxone (10(-5) M). Results are expressed as percent of Ach contractions. In our study, we showed that in guinea pig ileum the peptide A (k opioid receptor antagonist) was able to induce a strong contracture at a concentration of 10(-9) M when injected 4 min after U50-488H (10(-8) M). Also, in rabbit jejunum the peptide B (delta-opioid receptor antagonist) was able to induce a strong contracture at a concentration of 10(-10) M when injected 4 min after deltorphin II (10(-8) M). The results of our experiments indicate that both peptide A (k receptor opiod antagonist) and peptide B (alpha receptor opioid antagonist) showed an antagonistic activity higher than naloxone.
authors.affiliation: Department of Pharmaceutical Sciences, University of Salerno, via Ponte Don Melillo (84084) Fisciano (Salerno), Italy. annacap@unisa.it
authors.forename: A
authors.initials: A
authors.lastname: Capasso
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007583:Jejunum / Q000187:drug effects / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011817:Rabbits; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D010455:Peptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; C060209:deltorphin II, Ala(2)-; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins