Side Chain Methyl Substitution in the δ-Opioid Receptor Antagonist TIPP Has an Important Effect on the Activity Profile

• Published in: Journal of medicinal chemistry 1998-12, Vol.41 (26), p.5167-5176
• Main Authors: Tourwé, Dirk, Mannekens, Els, Diem, Trang Nguyen Thi, Verheyden, Patricia, Jaspers, Hendrika, Tóth, Géza, Péter, Antal, Kertész, István, Török, Gabriella, Chung, Nga N, Schiller, Peter W
• Format: Article
• Language: English
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Cell Line; Cerebellum - drug effects; Cerebellum - metabolism; Guinea Pigs; Ileum - drug effects; Ileum - physiology; In Vitro Techniques; Male; Medical sciences; Mice; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Narcotic Antagonists - chemical synthesis; Narcotic Antagonists - chemistry; Narcotic Antagonists - metabolism; Narcotic Antagonists - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - metabolism; Oligopeptides - pharmacology; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Prosencephalon - drug effects; Prosencephalon - metabolism; Protein Conformation; Radioligand Assay; Rats; Receptors, Opioid, delta - agonists; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, mu - agonists; Structure-Activity Relationship; Tetrahydroisoquinolines; Vas Deferens - drug effects; Vas Deferens - physiology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm981011u

The δ-opioid antagonist H-Tyr-Tic-Phe-Phe-OH (TIPP-OH) or its C-terminal amide analogue was systematically modified topologically by substitution of each amino acid residue by all stereoisomers of the corresponding β-methyl amino acid. The potency and selectivity (δ- vs μ- and κ-opioid receptor) were evaluated by radioreceptor binding assays. Agonist or antagonist potency were assayed in the mouse vas deferens and in the guinea pig ileum. In the TIPP analogues containing l-β-methyl amino acids the influence on δ-receptor affinity and on δ-antagonist potency is limited, the [(2S,3R)-β-MePhe3]TIPP-OH analogue being among the most potent δ-antagonists reported. In the d-β-methyl amino acid series, the [d-β-MeTic2] analogues are δ-selective antagonists whereas [d-Tic2]TIPP-NH2 is a δ-agonist. NMR studies did not indicate any influence of the β-methyl substituent on the conformation of the Tic residue. The [(2R,3S)-β-MePhe3]TIPP-NH2 is a potent δ-agonist, its C-terminal carboxylic acid analogue being more δ-selective but displaying partial agonism in both the δ- and μ-bioassay. These results constitute further examples of a profound influence of β-methyl substitution on the potency, selectivity, and signal transduction properties of a peptide.