Design and Synthesis of Potent Cystine-Free Cyclic Hexapeptide Agonists at the Human Urotensin Receptor

• Published in: Organic letters Vol. 8; no. 9; pp. 1799 - 1802
• Main Authors: Foister, Shane, Taylor, Laurie L, Feng, Jin-Jye, Chen, Wen-Long, Lin, Atsui, Cheng, Fong-Chi, Smith, Amos B, Hirschmann, Ralph
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.04.2006; Amer Chemical Soc
• Subjects: Amino Acid Sequence; Binding Sites; Chemistry; Chemistry, Organic; Cystine - chemistry; Dipeptides - chemistry; Humans; Models, Molecular; Molecular Structure; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Physical Sciences; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - chemistry; Science & Technology; Urotensins - agonists; Urotensins - chemistry; SOMATOSTATIN ANALOGS; RAT; CONTRACTION; CLONING; VASOCONSTRICTOR; CARDIOVASCULAR-DISEASE; ANTAGONISTS; II-RECEPTOR; EXPRESSION; PEPTIDE
• ISSN: 1523-7060; 1523-7052
• DOI: 10.1021/ol060278h

Cyclic hexapeptides, incorporating a dipeptide unit in place of the disulfide bond found in urotensin, were prepared and screened at the human urotensin receptor. The bridging dipeptide unit was found to influence dramatically the affinity for the urotensin receptor. Alanyl-N-methylalanyl and alanylprolyl dipeptide bridges failed to afford active ligands, while the alanyl-alanyl unit yielded a ligand with submicromolar affinity for the urotensin receptor. Further development led to a hexapeptide agonist with nanomolar affinity (2.8 nM).