The Dmt-Tic pharmacophore exhibits potent δ-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 δ affinity (1', 2, 7, and 9), but exhibited low to non-selectivity toward μ receptors similar to H-Dmt-Tic-amide and H-Dmt-Tic-ol. Functional bioactivity indicated high δ antagonism (pA2 7.4-7.9) (1', 2, and 9) and modest μ agonism, pEC50 (6.1-6.3) (1', 2, 8, and 9), but with E(max) values analogous to dermorphin. These Dmt-Tic analogues with mixed b antagonist/μ agonist properties would appear to be better candidates as analgesics than pure μ agonists. (C) 2000 Elsevier Science Ltd.
Assessment of substitution in the second pharmacophore of Dmt-Tic analogues
BALBONI, Gianfranco;GUERRINI, Remo;SALVADORI, Severo;
2000
Abstract
The Dmt-Tic pharmacophore exhibits potent δ-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 δ affinity (1', 2, 7, and 9), but exhibited low to non-selectivity toward μ receptors similar to H-Dmt-Tic-amide and H-Dmt-Tic-ol. Functional bioactivity indicated high δ antagonism (pA2 7.4-7.9) (1', 2, and 9) and modest μ agonism, pEC50 (6.1-6.3) (1', 2, 8, and 9), but with E(max) values analogous to dermorphin. These Dmt-Tic analogues with mixed b antagonist/μ agonist properties would appear to be better candidates as analgesics than pure μ agonists. (C) 2000 Elsevier Science Ltd.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
