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

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Abstract

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 (EC50=6.35 nM, Emax=−18.87%) for [35S]GTPγS binding and H-Dmt–Tic-NH2 was a neutral antagonist (no effect up to 30 μM). In contrast N,N(CH3)2-Dmt–Tic-NH2 was a full inverse agonist (EC50=2.66 nM, Emax=−35.95%) similar to ICI 174864 ([N,N-diallyl-Tyr1,Aib2,3,Leu5]enkephaline) but with a 3.5-fold higher EC50. In comparison, naltrindole was a neutral antagonist while its analogue HS 378 was a partial inverse agonist (Emax=−12.99%).

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