A series of 17 analogues were developed on the basis of the general formula H-Dmt-Tic-NH-*CH(R)-R' (* denotes chirality; R = charged, neutral, or aromatic functional group; R' = -OH or -NH2). These compounds were designed to test the following hypothesis: the physicochemical properties of third-residue substitutions C-terminal to Tic in the Dmt-Tic pharmacophore modify delta-opioid receptor selectivity and delta-opioid receptor antagonism through enhanced interactions with they-opioid receptor. The data substantiate the following conclusions: (i) all compounds had high receptor affinity [K-i(delta) = 0.034-1.1 nM], while that for the mu-opioid receptor fluctuated by orders of magnitude [K-i(mu) = 15.1-3966 nM]; (ii) delta-opioid receptor selectivity [K-i(mu)/Ki(delta)] declined 1000-fold from 22 600 to 21; (iii) a C-terminal carboxyl. group enhanced selectivity but only as a consequence of the specific residue; (iv) amidated, positive charged residues [Lys-NH2 (6), Arg-NH2 (7)], and a negatively charged aromatic residue [Trp-OH (11)] enhanced mu-opioid affinity [Ki(mu) = 17.0, 15.1, and 15.7 nM, respectively], while Gly-NH2 (8), Ser-NH2 (10), and His-OH (12) were nearly one-tenth as active; and M D-isomers exhibited mixed effects on mu-opioid receptor affinity (2' much less than 3' < 4' < 1' < 5') and decreased 6-selectivity in D-Asp-NH2 (1') and D-Lys(Ac)-OH (5'). The analogues exhibited delta-opioid receptor antagonism (pA(2) = 6.9-10.07) and weak mu-opioid receptor agonism (IC50 > 1 muM) except H-Dmt-Tic-Glu-NH2 (3), which was a partial delta-opioid receptor agonist (IC50 = 2.5 nM). Thus, these C-terminally extended analogues indicated that an amino acid residue containing a single charge, amino or guanidino functionality, or aromatic group substantially altered the delta-opioid receptor activity profile (selectivity and antagonism) of the Dmt-Tic pharmacophore, which suggests that the C-terminal constituent plays a major role in determining opioid receptor activity as an "address domain".
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