Conformationally Constrained Deltorphin Analogs with 2-Aminotetralin-2-Carboxylic Acid in Position 3

• Published in: Journal of medicinal chemistry 1997-03, Vol.40 (6), p.990-995
• Main Authors: Tóth, Géza, Darula, Zsuzsa, Péter, Antal, Fülöp, Ferenc, Tourwé, Dirk, Jaspers, Hendrika, Verheyden, Patricia, Böcskey, Zsolt, Tóth, Zoltán, Borsodi, Anna
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - chemical synthesis; Analgesics, Opioid - chemistry; Analgesics, Opioid - metabolism; Analgesics, Opioid - pharmacology; Animals; Binding, Competitive; Biological and medical sciences; Brain - metabolism; Guinea Pigs; Ileum - drug effects; Magnetic Resonance Spectroscopy; Male; Medical sciences; Mice; Muscle Contraction - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - metabolism; Oligopeptides - pharmacology; Opioid Peptides - chemical synthesis; Opioid Peptides - chemistry; Opioid Peptides - metabolism; Opioid Peptides - pharmacology; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Protein Binding; Protein Conformation; Rats; Receptors, Opioid, delta - agonists; Receptors, Opioid, delta - metabolism; Vas Deferens - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9602726

Two approaches to the design of very active and highly selective δ opioid peptides were used to obtain new deltorphin analogs with altered hydrophobic and stereoelectronic properties. Deltorphin I and II analogs were synthesized involving the substitution of Ile instead of Val at positions 5 and 6 in the address domain and 2-aminotetralin-2-carboxylic acid (Atc) instead of Phe in the message domain. The peptides were agonists in the subnanomolar range in the MVD assay and in the micromolar or higher range in the GPI assay, showing a very high selectivity for δ receptors. A very similar trend could be observed in radioreceptor binding assays in which selective tritiated opioid ligands were used. (R)- and (S)-Atc-deltorphins exhibited similar K i values in the binding assay, with almost complete loss of the stereospecificity of the binding. Conformational studies provided evidence for little disturbance of the backbone conformational equilibrium when Phe3 is replaced by (S)- or (R)-Atc. The use of the Atc constraint gives additional evidence that, during its interaction with the δ receptor, the side chain of residue 3 adopts the trans conformation at χ1.