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

Abstract

Twenty N- and/or C-modified Dmt-Tic analogues yielded similar K_i 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 (K_i = 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 (K_iδ = 0.16 nM and K_iμ = 1.12 nM) and potent δ antagonism (pA₂ = 9.06) with μ agonism (IC₅₀ = 16 nM). H-Dmt-βHTic-OH (methylene bridge between C_α of Tic and carboxylate function) yielded a biostable peptide with high δ affinity (K_i = 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 (K_i = 0.06 to 0.2 nM) and elevated μ affinities (K_i = 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.