Further Studies on the Dmt-Tic Pharmacophore: Hydrophobic Substituents at the C-Terminus Endow delta Antagonists To Manifest mu Agonism or mu Antagonism

Twenty N- and/or C-modified Dmt-Tic analogues yielded similar Ki values with either [3H]- DPDPE (ä1 agonist) or [3H]N,N(Me)2-Dmt-Tic-OH (ä antagonist). N-Methylation enhanced ä antagonism while N-piperidine-1-yl, N-pyrrolidine-1-yl, and N-pyrrole-1-yl were detrimental. Dmt-Tic-X (X)-NHNH2, -NHCH3, -NH-1-adamantyl, -NH-tBu, -NH-5-tetrazolyl) had high ä affinities (Ki ) 0.16 to 1 nM) with variable í affinities to yield nonselective or weakly í-selective analogues. N,N-(Me)2Dmt-Tic-NH-1-adamantane exhibited dual ä and í receptor affinities (Kiä ) 0.16 nM and Kií ) 1.12 nM) and potent ä antagonism (pA2 ) 9.06) with í agonism (IC50 ) 16 nM). H-Dmt-âHTic-OH (methylene bridge between CR of Tic and carboxylate function) yielded a biostable peptide with high ä affinity (Ki ) 0.85 nM) and ä antagonism (pA2 ) 8.85) without í bioactivity. Dmt-Tic-Ala-X (X ) -NHCH3, -OCH3, -NH-1-adamantyl, -NHtBu) exhibited high ä affinities (Ki ) 0.06 to 0.2 nM) and elevated í affinities (Ki ) 2.5 to 11 nM), but only H-Dmt-Tic-Ala-NH-1-adamantane and H-Dmt-Tic-Ala-NHtBu yielded ä receptor antagonism (pA2 ) 9.29 and 9.16, respectively). Thus, Dmt-Tic with hydrophobic C-terminal substituents enhanced í affinity to provide ä antagonists with dual receptor affinities and bifunctional activity.