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

Abstract

Substitution of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic 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 κ, δ, and μ receptors, and κ 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 κ-sites while the affinities for δ- and μ-receptors remained essentially unchanged. The doubly substituted analogue [2′,6′-dimethyl- l-tyrosine (Dmt 1)-Tic 2]DYN ( 3) exhibited high δ-affinity ( K i = 0.39 nM) while μ- and κ-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 δ- and κ-antagonism, while the δ agonist potency of 4 was comparable to DYN. Thus, conversion from a κ-agonist to antagonist occurred with the inclusion of Tic into DYN analogues, similar to the appearance of antagonist properties with δ- and μ-opioid agonists containing a Tic 2 residue.