Design, Synthesis and Pharmacological Characterization of Novel Calcitonin Gene-Related Peptide Receptor Antagonists
type: CreativeWork
description: ABSTRACT|Human-a-calcitonin gene-related peptide (CGRP) is a 37 amino acid residue neuropeptide produced from tissue-specific alternative splicing of the primary RNA transcript of the calcitonin gene. CGRP is widely distributed throughout the central and peripheral nervous systems and is involved in wound healing, inflammatory responses, nociception, appetite suppression, gastric emptying, regulation of vascular tone and regional organ blood flow.|The conformation of CGRP, defined in CD and two-dimensional 1H-NMR studies, includes a disulfide bridged N-terminal ring structure between residues 2 and 7, an amphipathic a-helical segment between residues 8 through 18 which ends in a ß-turn centered on residues 19 through 22 and a conformationally disordered C-terminus. Molecular modeling studies suggest a turn structure centered on residue 33 exists. Previous studies have shown that the N-terminal loop of CGRP is required for the activation of signal transduction by CGRP receptors. Truncation of the N-terminal ring, resulting in CGRP(8-37), leads to loss of agonist activity while retaining the ability to bind to the receptor and CGRP(8-37) became the primary research tool used to investigate CGRP receptors. The development of CGRP receptor antagonists has progressed slowly since the inception of the CGRP field. Further truncation of the N-terminus of CGRP(8-37) has resulted in antagonists at CGRP receptors with marked reductions in antagonist potency, suggesting that N-terminal structural elements of CGRP(8-37) are important for high affinity binding to CGRP receptors.|Previous studies in my lab described a series of N-termina!ly modified CGRP(8-37) analogs that were high affinity antagonists of calcitonin gene-related peptide receptors. These analogues, N-a-benzoyl-h-a-CGRP(8-37), N-a-benzyl- h-a-CGRP(8-37) and dibenzyl-h-cc-CGRP(8-37), all possess binding affinities for CGRP receptors, similar to the endogenous ligand CGRP, in the low nanomolar range. These studies sh…
abstract: ABSTRACT|Human-a-calcitonin gene-related peptide (CGRP) is a 37 amino acid residue neuropeptide produced from tissue-specific alternative splicing of the primary RNA transcript of the calcitonin gene. CGRP is widely distributed throughout the central and peripheral nervous systems and is involved in wound healing, inflammatory responses, nociception, appetite suppression, gastric emptying, regulation of vascular tone and regional organ blood flow.|The conformation of CGRP, defined in CD and two-dimensional 1H-NMR studies, includes a disulfide bridged N-terminal ring structure between residues 2 and 7, an amphipathic a-helical segment between residues 8 through 18 which ends in a ß-turn centered on residues 19 through 22 and a conformationally disordered C-terminus. Molecular modeling studies suggest a turn structure centered on residue 33 exists. Previous studies have shown that the N-terminal loop of CGRP is required for the activation of signal transduction by CGRP receptors. Truncation of the N-terminal ring, resulting in CGRP(8-37), leads to loss of agonist activity while retaining the ability to bind to the receptor and CGRP(8-37) became the primary research tool used to investigate CGRP receptors. The development of CGRP receptor antagonists has progressed slowly since the inception of the CGRP field. Further truncation of the N-terminus of CGRP(8-37) has resulted in antagonists at CGRP receptors with marked reductions in antagonist potency, suggesting that N-terminal structural elements of CGRP(8-37) are important for high affinity binding to CGRP receptors.|Previous studies in my lab described a series of N-termina!ly modified CGRP(8-37) analogs that were high affinity antagonists of calcitonin gene-related peptide receptors. These analogues, N-a-benzoyl-h-a-CGRP(8-37), N-a-benzyl- h-a-CGRP(8-37) and dibenzyl-h-cc-CGRP(8-37), all possess binding affinities for CGRP receptors, similar to the endogenous ligand CGRP, in the low nanomolar range. These studies sh…
author: Taylor, Christopher K.
language: en_US
date published: 2006-06
date modified: 2026-07-24T01:49:51Z
provider: Creighton University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Creighton University

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property ID: Handle
value: http://hdl.handle.net/10504/45473