Identification of Potent, Selective, and Metabolically Stable Peptide Antagonists to the Calcitonin Gene-Related Peptide (CGRP) Receptor

Calcitonin gene-related peptide (CGRP) is a 37-residue neuropeptide that can be converted to a CGRP1 receptor antagonist by the truncation of its first seven residues. CGRP(8−37), 1, has a CGRP1 receptor K i = 3.2 nM but is rapidly degraded in human plasma (t 1/2 = 20 min). As part of an effort to i...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-12, Vol.51 (24), p.7889-7897
Main Authors: Miranda, Les P, Holder, Jerry Ryan, Shi, Licheng, Bennett, Brian, Aral, Jennifer, Gegg, Colin V, Wright, Marie, Walker, Kenneth, Doellgast, George, Rogers, Rick, Li, Hongyan, Valladares, Violeta, Salyers, Kevin, Johnson, Eileen, Wild, Kenneth
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Biological and medical sciences
Chemistry, Pharmaceutical - methods
CHO Cells
Cricetinae
Cricetulus
Drug Design
Humans
Inhibitory Concentration 50
Kinetics
Macaca fascicularis
Male
Medical sciences
Molecular Conformation
Molecular Sequence Data
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Protein Binding
Receptors, Calcitonin Gene-Related Peptide - antagonists & inhibitors
Receptors, Calcitonin Gene-Related Peptide - chemistry
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Summary:Calcitonin gene-related peptide (CGRP) is a 37-residue neuropeptide that can be converted to a CGRP1 receptor antagonist by the truncation of its first seven residues. CGRP(8−37), 1, has a CGRP1 receptor K i = 3.2 nM but is rapidly degraded in human plasma (t 1/2 = 20 min). As part of an effort to identify a prolonged in vivo circulating CGRP peptide antagonist, we found that the substitution of multiple residues in the CGRP peptide increased CGRP1 receptor affinity >50-fold. Ac-Trp-[Arg24,Lys25,Asp31,Pro34,Phe35]CGRP(8−37)-NH2, 5 (K i = 0.06 nM) had the highest CGRP1 receptor affinity. Using complimentary in vitro and in vivo metabolic studies, we iteratively identified degradation sites and prepared high affinity analogues with significantly improved plasma stability. Ac-Trp-[Cit11,18,hArg24,Lys25,2-Nal27,37,Asp31,Oic29,34,Phe35]CGRP(8−37)-NH2, 32 (K i = 3.3 nM), had significantly increased (>100-fold) stability over 1 or 5, with a cynomolgus monkey and human in vitro plasma half-life of 38 and 68 h, respectively.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm8009298