Rational design of dynorphin A analogues with δ-receptor selectivity and antagonism for δ- and κ-receptors

Substitution of 1,2,3,4-tetrahydroisoquinoline-3-carboxyl acid (Tic) in place of Gly(2) in dynorphin A-(1-13)-NH(2) and -(1-11)-NH(2) (DYN) analogues (1 and 2) decreased the affinity to the kappa, delta, and mu receptors, and kappa selectivity. The analogue [D-Ala(2), des-Gly(3)]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 (Dmt(1))-Tic(2)]DYN (3) exhibited high delta-affnity (K(1) = 0.39 nM) while mu- and kappa-affinities were only an order of magnitude less (4-5 nM). Bioactivity of [Tic(2)]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 Tic(2) residue. (C) 1998 Elsevier Science Ltd. All rights reserved.