Assessment of substitution in the second pharmacophore of Dmt-Tic analogues

The Dmt-Tic pharmacophore exhibits potent delta -opioid receptor antagonism . Analogues with substitutions in the second pharmacophore with (1, 1') or without a COOH function (2-9) were synthesized: several had high delta affi nity (1', 2, 7, and 9), but exhibited low to non-selectivity toward mu rece ptors similar to H-Dmt-Tic-amide and H-Dmt Tic-ol. Functional bioactivity i ndicated high delta antagonism (pA(2) 7.4-7.9) (1', 2, and 9) and modest mu agonism, pEC(50) (6.1-6.3) (1', 2, 8, and 9), but with E-max values analog ous to dermorphin. These Dmt-Tic analogues with mixed delta antagonist/mu a gonist properties would appear to be better candidates as analgesics than p ure mu agonists. (C) 2000 Elsevier Science Ltd. All rights reserved.