Synthesis and biological evaluation of constrained analogues of the opioid peptide H-Tyr-d-Ala-Phe-Gly-NH2 using the 4-amino-2-benzazepin-3-one scaffold

• Published in: The journal of peptide research 2005-11, Vol.66 (5), p.222-230
• Main Authors: Ballet, S., Frycia, A., Piron, J., Chung, N.N., Schiller, P.W., Kosson, P., Lipkowski, A.W., Tourwé, D.
• Format: Article
• Language: English
• Subjects: 4-amino-1; 4‐amino‐1,2,4,5‐tetrahydro‐2‐benzazepin‐3‐one scaffold; 5-tetrahydro-2-benzazepin-3-one scaffold; Animals; conformational restriction; dermorphin analogues; Dose-Response Relationship, Drug; Male; Molecular Structure; Oligopeptides - chemical synthesis; Opioid Peptides - chemical synthesis; Opioid Peptides - chemistry; Protein Conformation; Rats; Rats, Sprague-Dawley; Receptors, Opioid - chemistry; Receptors, Opioid - metabolism; Structure-Activity Relationship; Time Factors
• ISSN: 1397-002X; 1399-3011
• DOI: 10.1111/j.1399-3011.2005.00291.x

:  The synthesis of conformationally restricted dipeptidic moieties 4‐amino‐1,2,4,5‐tetrahydro‐2‐benzazepin‐3‐one (Aba)‐Gly ([(4S)‐amino‐3‐oxo‐1,2,4,5‐tetrahydro‐1H‐2‐benzazepin‐2‐yl]‐acetic acid) and 8‐hydroxy‐4‐amino‐1,2,4,5‐tetrahydro‐2‐benzazepin‐3‐one (Hba)‐d‐Ala ([(4S)‐amino‐8‐hydroxy‐3‐oxo‐1,2,4,5‐tetrahydro‐benzo[c]azepin‐2‐yl]‐propionic acid) was based on a synthetic strategy that uses an oxazolidinone as an N‐acyliminium precursor. Introducing these Aba scaffolds into the N‐terminal tetrapeptide of dermorphin (H‐Tyr‐d‐Ala‐Phe‐Gly‐Tyr‐Pro‐Ser‐NH2)‐induced remarkable shifts in affinity and selectivity towards the opioid μ‐ and δ‐receptors. This paper provides the synthesis and biological in vitro and in vivo evaluation of constricted analogues of the N‐terminal tetrapeptide H‐Tyr‐d‐Ala‐Phe‐Gly‐NH2, which is the minimal subunit of dermorphin needed for dermorphin‐like opiate activity.