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

Publisher Website
Google Scholar
Abstract
Twenty N- and/or C-modified Dmt-Tic analogues yielded similar Ki values with either [3H]DPDPE (δ1 agonist) or [3H]N,N(Me)2-Dmt-Tic-OH (δ antagonist). N-Methylation enhanced δ 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 δ affinities (Ki = 0.16 to 1 nM) with variable μ affinities to yield nonselective or weakly μ-selective analogues. N,N-(Me)2Dmt-Tic-NH-1-adamantane exhibited dual δ and μ receptor affinities (Kiδ = 0.16 nM and Kiμ = 1.12 nM) and potent δ antagonism (pA2 = 9.06) with μ agonism (IC50 = 16 nM). H-Dmt-βHTic-OH (methylene bridge between Cα of Tic and carboxylate function) yielded a biostable peptide with high δ affinity (Ki = 0.85 nM) and δ antagonism (pA2 = 8.85) without μ bioactivity. Dmt-Tic-Ala-X (X = −NHCH3, −OCH3, −NH-1-adamantyl, −NHtBu) exhibited high δ affinities (Ki = 0.06 to 0.2 nM) and elevated μ affinities (Ki = 2.5 to 11 nM), but only H-Dmt-Tic-Ala-NH-1-adamantane and H-Dmt-Tic-Ala-NHtBu yielded δ receptor antagonism (pA2 = 9.29 and 9.16, respectively). Thus, Dmt-Tic with hydrophobic C-terminal substituents enhanced μ affinity to provide δ antagonists with dual receptor affinities and bifunctional activity.