Influence of the Side Chain Next to C-Terminal Benzimidazole in Opioid Pseudopeptides Containing the Dmt-Tic Pharmacophore

• Published in: Journal of medicinal chemistry 2009-09, Vol.52 (17), p.5556-5559
• Main Authors: Balboni, Gianfranco, Trapella, Claudio, Sasaki, Yusuke, Ambo, Akihiro, Marczak, Ewa D, Lazarus, Lawrence H, Salvadori, Severo
• Format: Article
• Language: English
• Subjects: Animals; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - metabolism; Benzimidazoles - pharmacology; Biological and medical sciences; Dipeptides - chemistry; Humans; Inhibitory Concentration 50; Medical sciences; Narcotic Antagonists - chemical synthesis; Narcotic Antagonists - chemistry; Narcotic Antagonists - metabolism; Narcotic Antagonists - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Receptors, Opioid - metabolism; Substrate Specificity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900686q

To improve the structure−activity studies of the lead δ opioid agonist H-Dmt-Tic-Asp*-Bid, we synthesized and pharmacologically characterized a series of analogues in which the side chain next to 1H-benzimidazole-2-yl (Bid) was substituted by those endowed with different chemical properties. Interesting results were obtained: (1) only Gly, Ala, and Asp resulted in δ agonism, (2) Phe yielded δ antagonism, (3) and all other residues except Glu (devoid of any activity) gave μ agonism.