Pharmacological characterization of novel α-calcitonin gene-related peptide (CGRP) receptor peptide antagonists that are selective for human CGRP receptors

Christopher K. Taylor, D. David Smith, Martin Hulce, Peter W. Abel

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Human α-calcitonin gene-related peptide (CGRP) is a 37-residue neuropeptide that produces a variety of cardiovascular and other effects via activation of specific CGRP receptors that produce cAMP. Functional CGRP receptors are a heterodimeric complex composed of the heptahelical calcitonin receptor-like receptor and the single transmembrane receptor activity-modifying protein 1. Based on the known structures of the antagonist CGRP(8-37) and the human CGRP receptor, we designed novel CGRP receptor peptide antagonists with modifications to promote high affinity and selectivity for human CGRP receptors. Antagonist affinity (KB) at CGRP receptors was determined using the mouse thoracic aorta and human SK-N-MC cells. In aorta, CGRP(8-37), [N-α-benzoyl]human α-CGRP(8-37) [bzl-CGRP(8-37)], and [N-α-benzoyl-His10-benzyl] human α-CGRP(8-37) [bzl-bn-CGRP(8-37)] caused rightward shifts in the concentration-response relaxation curve for CGRP with KB values of 1000, 88, and 50 nM, respectively. In human SK-N-MC cells, CGRP(8-37), bzl-CGRP(8-37), and bzl-bn-CGRP (8-37) caused rightward shifts in the concentration-response curve for CGRP-stimulated cAMP production with KB values of 797, 15, and 0.63 nM, respectively. Thus, CGRP(8-37) had the same affinity for human and mouse CGRP receptors, whereas bzl-CGRP(8-37) and bzl-bn-CGRP(8-37) displayed 6-and 80-fold higher affinities, respectively, for human CGRP receptors. In addition, the selectivity of the antagonists for human CGRP receptors was highly correlated with the antagonist hydrophobicity index. These relatively high-affinity, species-selective peptide antagonists provide novel tools to differentiate structural and functional features that are unique to the human CGRP receptor. Thus, these analogs may be useful compounds for development of drugs to treat migraine headache and other cardiovascular diseases.

Original languageEnglish
Pages (from-to)749-757
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume319
Issue number2
DOIs
StatePublished - 2006

Fingerprint

Calcitonin Gene-Related Peptide Receptors
Pharmacology
Peptides
Calcitonin Gene-Related Peptide
Receptor Activity-Modifying Protein 1
Calcitonin Receptor-Like Protein
calcitonin gene-related peptide (8-37)
Neuropeptides
Migraine Disorders
Thoracic Aorta
Hydrophobic and Hydrophilic Interactions
Aorta
Cardiovascular Diseases

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

@article{7adf6b0408de4432a2c53e2acba63e8b,
title = "Pharmacological characterization of novel α-calcitonin gene-related peptide (CGRP) receptor peptide antagonists that are selective for human CGRP receptors",
abstract = "Human α-calcitonin gene-related peptide (CGRP) is a 37-residue neuropeptide that produces a variety of cardiovascular and other effects via activation of specific CGRP receptors that produce cAMP. Functional CGRP receptors are a heterodimeric complex composed of the heptahelical calcitonin receptor-like receptor and the single transmembrane receptor activity-modifying protein 1. Based on the known structures of the antagonist CGRP(8-37) and the human CGRP receptor, we designed novel CGRP receptor peptide antagonists with modifications to promote high affinity and selectivity for human CGRP receptors. Antagonist affinity (KB) at CGRP receptors was determined using the mouse thoracic aorta and human SK-N-MC cells. In aorta, CGRP(8-37), [N-α-benzoyl]human α-CGRP(8-37) [bzl-CGRP(8-37)], and [N-α-benzoyl-His10-benzyl] human α-CGRP(8-37) [bzl-bn-CGRP(8-37)] caused rightward shifts in the concentration-response relaxation curve for CGRP with KB values of 1000, 88, and 50 nM, respectively. In human SK-N-MC cells, CGRP(8-37), bzl-CGRP(8-37), and bzl-bn-CGRP (8-37) caused rightward shifts in the concentration-response curve for CGRP-stimulated cAMP production with KB values of 797, 15, and 0.63 nM, respectively. Thus, CGRP(8-37) had the same affinity for human and mouse CGRP receptors, whereas bzl-CGRP(8-37) and bzl-bn-CGRP(8-37) displayed 6-and 80-fold higher affinities, respectively, for human CGRP receptors. In addition, the selectivity of the antagonists for human CGRP receptors was highly correlated with the antagonist hydrophobicity index. These relatively high-affinity, species-selective peptide antagonists provide novel tools to differentiate structural and functional features that are unique to the human CGRP receptor. Thus, these analogs may be useful compounds for development of drugs to treat migraine headache and other cardiovascular diseases.",
author = "Taylor, {Christopher K.} and Smith, {D. David} and Martin Hulce and Abel, {Peter W.}",
year = "2006",
doi = "10.1124/jpet.106.108316",
language = "English",
volume = "319",
pages = "749--757",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Pharmacological characterization of novel α-calcitonin gene-related peptide (CGRP) receptor peptide antagonists that are selective for human CGRP receptors

AU - Taylor, Christopher K.

AU - Smith, D. David

AU - Hulce, Martin

AU - Abel, Peter W.

PY - 2006

Y1 - 2006

N2 - Human α-calcitonin gene-related peptide (CGRP) is a 37-residue neuropeptide that produces a variety of cardiovascular and other effects via activation of specific CGRP receptors that produce cAMP. Functional CGRP receptors are a heterodimeric complex composed of the heptahelical calcitonin receptor-like receptor and the single transmembrane receptor activity-modifying protein 1. Based on the known structures of the antagonist CGRP(8-37) and the human CGRP receptor, we designed novel CGRP receptor peptide antagonists with modifications to promote high affinity and selectivity for human CGRP receptors. Antagonist affinity (KB) at CGRP receptors was determined using the mouse thoracic aorta and human SK-N-MC cells. In aorta, CGRP(8-37), [N-α-benzoyl]human α-CGRP(8-37) [bzl-CGRP(8-37)], and [N-α-benzoyl-His10-benzyl] human α-CGRP(8-37) [bzl-bn-CGRP(8-37)] caused rightward shifts in the concentration-response relaxation curve for CGRP with KB values of 1000, 88, and 50 nM, respectively. In human SK-N-MC cells, CGRP(8-37), bzl-CGRP(8-37), and bzl-bn-CGRP (8-37) caused rightward shifts in the concentration-response curve for CGRP-stimulated cAMP production with KB values of 797, 15, and 0.63 nM, respectively. Thus, CGRP(8-37) had the same affinity for human and mouse CGRP receptors, whereas bzl-CGRP(8-37) and bzl-bn-CGRP(8-37) displayed 6-and 80-fold higher affinities, respectively, for human CGRP receptors. In addition, the selectivity of the antagonists for human CGRP receptors was highly correlated with the antagonist hydrophobicity index. These relatively high-affinity, species-selective peptide antagonists provide novel tools to differentiate structural and functional features that are unique to the human CGRP receptor. Thus, these analogs may be useful compounds for development of drugs to treat migraine headache and other cardiovascular diseases.

AB - Human α-calcitonin gene-related peptide (CGRP) is a 37-residue neuropeptide that produces a variety of cardiovascular and other effects via activation of specific CGRP receptors that produce cAMP. Functional CGRP receptors are a heterodimeric complex composed of the heptahelical calcitonin receptor-like receptor and the single transmembrane receptor activity-modifying protein 1. Based on the known structures of the antagonist CGRP(8-37) and the human CGRP receptor, we designed novel CGRP receptor peptide antagonists with modifications to promote high affinity and selectivity for human CGRP receptors. Antagonist affinity (KB) at CGRP receptors was determined using the mouse thoracic aorta and human SK-N-MC cells. In aorta, CGRP(8-37), [N-α-benzoyl]human α-CGRP(8-37) [bzl-CGRP(8-37)], and [N-α-benzoyl-His10-benzyl] human α-CGRP(8-37) [bzl-bn-CGRP(8-37)] caused rightward shifts in the concentration-response relaxation curve for CGRP with KB values of 1000, 88, and 50 nM, respectively. In human SK-N-MC cells, CGRP(8-37), bzl-CGRP(8-37), and bzl-bn-CGRP (8-37) caused rightward shifts in the concentration-response curve for CGRP-stimulated cAMP production with KB values of 797, 15, and 0.63 nM, respectively. Thus, CGRP(8-37) had the same affinity for human and mouse CGRP receptors, whereas bzl-CGRP(8-37) and bzl-bn-CGRP(8-37) displayed 6-and 80-fold higher affinities, respectively, for human CGRP receptors. In addition, the selectivity of the antagonists for human CGRP receptors was highly correlated with the antagonist hydrophobicity index. These relatively high-affinity, species-selective peptide antagonists provide novel tools to differentiate structural and functional features that are unique to the human CGRP receptor. Thus, these analogs may be useful compounds for development of drugs to treat migraine headache and other cardiovascular diseases.

UR - http://www.scopus.com/inward/record.url?scp=33751165490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33751165490&partnerID=8YFLogxK

U2 - 10.1124/jpet.106.108316

DO - 10.1124/jpet.106.108316

M3 - Article

VL - 319

SP - 749

EP - 757

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -