Inverse agonism by Dmt–Tic analogues and HS 378, a naltrindole analogue

The potent δ-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 [ 35S]GTPγS binding and H-Dmt–Tic-NH 2 was a neutral antagonist (no effect up to 30 μM). 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%).