title: Calcitonin gene-related peptide analogues with aza and indolizidinone amino acid residues reveal conformational requirements for antagonist activity at the human calcitonin gene-related peptide 1 receptor.
abstract: Calcitonin gene-related peptide antagonists have potential for the treatment and prevention of disease states such as non-insulin-dependent diabetes mellitus, migraine headache, pain, and inflammation. To gain insight into the spatial requirements for CGRP antagonism, three strategies were employed to restrict the conformation of the potent undecapeptide antagonist, [D31,P34,F35]CGRP27-37. First, aza-amino acid scanning was performed, and ten aza-peptide analogues were synthesized and examined for biological activity. Second, (3S,6S,9S)-2-oxo-3-amino-indolizidin-2-one amino acid (I2aa) and (2S,6S,8S)-9-oxo-8-amino-indolizidin-9-one amino acid (I9aa) both were introduced at positions 31-32, 32-33, 33-34, and 34-35, regions of the backbone expected to adopt turns. Finally, the conformation of the backbone and side-chain of the C-terminal residue, Phe35-Ala36-Phe37-NH2, was explored employing (2S,4R,6R,8S)-9-oxo-8-amino-4-phenyl-indolizidin-9-one amino acid (4-Ph-I9aa) as a constrained phenylalanine mimic. The structure-activity relationships exhibited by our 26 analogues illustrate conformational requirements important for designing CGRP antagonists and highlight the importance of beta-turns centered at Gly33-Pro34 for potency.
authors.affiliation: Département de Chimie, Université de Montréal, C. P. 6128, Succursale Centre Ville, Montréal, Québec, Canada H3C 3J7.
authors.forename: Damien
authors.initials: D
authors.lastname: Boeglin
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Rosa E
authors.initials: RE
authors.lastname: Melendez
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cluzeau
authors.forename: Andre
authors.initials: A
authors.lastname: Laperriere
authors.forename: Madeleine
authors.initials: M
authors.lastname: Héroux
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
authors.forename: William D
authors.initials: WD
authors.lastname: Lubell
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D001372:Aza Compounds / Q000737:chemistry*; D015740:Calcitonin Gene-Related Peptide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D007212:Indolizines / Q000737:chemistry*; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D001372:Aza Compounds; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007212:Indolizines; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide