Bifunctional [2‘,6‘-Dimethyl-l-tyrosine]endomorphin-2 Analogues Substituted at Position 3 with Alkylated Phenylalanine Derivatives Yield Potent Mixed μ-Agonist/δ-Antagonist and Dual μ-Agonist/δ-Agonist Opioid Ligands

• Published in: Journal of medicinal chemistry 2007-06, Vol.50 (12), p.2753-2766
• Main Authors: Li, Tingyou, Shiotani, Kimitaka, Miyazaki, Anna, Tsuda, Yuko, Ambo, Akihiro, Sasaki, Yusuke, Jinsmaa, Yunden, Marczak, Ewa, Bryant, Sharon D, Lazarus, Lawrence H, Okada, Yoshio
• Format: Article
• Language: English
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Brain - metabolism; Guinea Pigs; In Vitro Techniques; Ligands; Male; Medical sciences; Mice; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - innervation; Muscle, Smooth - physiology; Myenteric Plexus - physiology; Neuromuscular Junction - drug effects; Neuromuscular Junction - physiology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oligopeptides - chemical synthesis; Oligopeptides - pharmacology; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta - agonists; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, mu - agonists; Structure-Activity Relationship; Synaptosomes - metabolism; Tyrosine - analogs & derivatives; Tyrosine - chemical synthesis; Tyrosine - pharmacology; Vas Deferens - drug effects; Vas Deferens - physiology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061238m

Endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH2) and [Dmt1]EM-2 (Dmt = 2‘,6‘-dimethyl-l-tyrosine) analogues, containing alkylated Phe3 derivatives, 2‘-monomethyl (2, 2‘), 3‘,5‘- and 2‘,6‘-dimethyl (3, 3‘, and 4‘, respectively), 2‘,4‘,6‘-trimethyl (6, 6‘), 2‘-ethyl-6‘-methyl (7, 7‘), and 2‘-isopropyl-6‘-methyl (8, 8‘) groups or Dmt (5, 5‘), had the following characteristics:  (i) [Xaa3]EM-2 analogues exhibited improved μ- and δ-opioid receptor affinities. The latter, however, were inconsequential (K i δ = 491−3451 nM). (ii) [Dmt1,Xaa3]EM-2 analogues enhanced μ- and δ-opioid receptor affinities (K i μ = 0.069−0.32 nM; K i δ = 1.83−99.8 nM) without κ-opioid receptor interaction. (iii) There were elevated μ-bioactivity (IC50 = 0.12−14.4 nM) and abolished δ-agonism (IC50 > 10 μM in 2‘, 3‘, 4‘, 5‘, 6‘), although 4‘ and 6‘ demonstrated a potent mixed μ-agonism/δ-antagonism (for 4‘, IC50 μ = 0.12 and pA 2 = 8.15; for 6‘, IC50 μ = 0.21 nM and pA 2 = 9.05) and 7‘ was a dual μ-agonist/δ-agonist (IC50 μ = 0.17 nM; IC50 δ = 0.51 nM).