Evolution of the Bifunctional Lead μ Agonist / δ Antagonist Containing the Dmt-Tic Opioid Pharmacophore.
ABSTRACT Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH(3), partially -NO(2), inactive -NH(2)) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA(2) = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.
Article: Differential stereochemical requirements of mu vs. delta opioid receptors for ligand binding and signal transduction: development of a class of potent and highly delta-selective peptide antagonists.[show abstract] [hide abstract]
ABSTRACT: Opioid peptide analogs consisting entirely of aromatic amino acid residues and containing conformationally restricted phenylalanine derivatives in position 2 of the peptide sequence were synthesized and pharmacologically characterized in vitro. Both diastereoisomers of H-Tyr-(D or L)-NMePhe-Phe-Phe-NH2 (NMePhe is N alpha-methylphenylalanine) were mu-receptor-selective, were full agonists in the mu-receptor-representative guinea pig ileum assay, and were partial agonists in the mouse vas deferens assay, with the L-NMePhe2 analog displaying somewhat higher intrinsic activity than the D-NMePhe2 analog. Further conformational restriction at position 2 in the sequence, as achieved through substitution of D- or L-tetrahydro-3-isoquinoline carboxylic acid (Tic), produced a configuration-dependent differential effect on receptor selectivity and intrinsic activity, leading to a potent mu-selective mu agonist (the D-Tic2 analog) with increased intrinsic activity in the mouse vas deferens assay and to a potent delta-selective delta antagonist (the L-Tic2 analog). These results demonstrate that imposition of conformational constraints in a peptide not only may alter receptor selectivity but also may decrease, totally abolish, or even enhance intrinsic activity. The tetrapeptide H-Tyr-Tic-Phe-Phe-NH2 was a moderately potent full agonist in the guinea pig ileum assay and, thus, represents a compound with mixed mu-agonist/delta-antagonist properties. The corresponding peptide with a free C-terminal carboxyl group H-Tyr-Tic-Phe-Phe-OH showed high delta-receptor affinity (Ki delta = 1.2 nM), unprecedented delta selectivity (Ki mu/Ki delta = 1410), high potency as delta antagonist (Ke = 3-8 nM against various delta agonists in the mouse vas deferens assay) and, unlike other delta antagonists, had no mu-antagonist properties. The tripeptides H-Tyr-Tic-Phe-OH and H-Tyr-Tic-Phe-NH2 were also delta antagonists.Proceedings of the National Academy of Sciences 01/1993; 89(24):11871-5. · 9.68 Impact Factor