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

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 κ, δ, and μ receptors, and κ selectivity. The analogue [d-Ala2, des-Gly3]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 (Dmt1)-Tic2]DYN (3) exhibited high δ-affinity (Ki = 0.39 nM) while μ- and κ-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 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 Tic2 residue.