Inverse agonism by Dmt-Tic analogues and H5 378, a naltrindole analogue

The potent delta-opioid receptor antagonist H-2',6-L-tyrosine(Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic-OH) exhibited partial inverse agonism (EC(50) = 6.35 nM, E(max) = - 18.87%) for [(35)S]GTP gamma S binding and H-Dmt-Tic-NH(2) was a neutral antagonist (no effect up to 30 mu M). In contrast N,N(CH(3))(2)-Dmt-Tic-NH(2) was a full inverse agonist (EC(50) = 2.66 nM, E(max) = -35.95%) similar to ICI 174864 ([N,N-diallyl-Tyr(1),Aib(2,3),Leu(5)]enkephaline) but with a 3.5-fold higher EC(50) In comparison, naltrindole was a neutral antagonist while its analogue HS 378 was a partial inverse agonist (E(max) = - 12.99%). (C) 2000 Elsevier Science B.V. All rights reserved.