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  • Rational design of dynorphin A analogues with delta-receptor selectivity and antagonism for delta- and kappa-receptors.

Rational design of dynorphin A analogues with delta-receptor selectivity and antagonism for delta- and kappa-receptors.

Bioorganic & medicinal chemistry (1998-03-21)
R Guerrini, A Capasso, M Marastoni, S D Bryant, P S Cooper, L H Lazarus, P A Temussi, S Salvadori
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.

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Sigma-Aldrich
(S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid, 97%
Sigma-Aldrich
1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid hydrochloride, 96%