Non-peptidic antagonists of the CGRP receptor, BIBN4096BS and MK-0974, interact with the calcitonin receptor-like receptor via methionine-42 and RAMP1 via tryptophan-74.

Biochemical and Biophysical Research Communications
Philip S MillerDan Donnelly

Abstract

The receptor for calcitonin gene-related peptide (CGRP) has been the target for the development of novel small molecule antagonists for the treatment of migraine. Two such antagonists, BIBN4096BS and MK-0974, have shown great promise in clinical trials and hence a deeper understanding of the mechanism of their interaction with the receptor is now required. The structure of the CGRP receptor is unusual since it is comprised of a hetero-oligomeric complex between the calcitonin receptor-like receptor (CRL) and an accessory protein (RAMP1). Both the CLR and RAMP1 components have extracellular domains which interact with each other and together form part of the peptide-binding site. It seems likely that the antagonist binding site will also be located on the extracellular domains and indeed Trp-74 of RAMP1 has been shown to form part of the binding site for BIBN4096BS. However, despite a chimeric study demonstrating the role of the N-terminal domain of CLR in antagonist binding, no specific residues have been identified. Here we carry out a mutagenic screen of the extreme N-terminal domain of CLR (residues 23-63) and identify a mutant, Met-42-Ala, which displays 48-fold lower affinity for BIBN4096BS and almost 900-fold lower affini...Continue Reading

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Citations

May 21, 2010·Expert Opinion on Investigational Drugs·Michael J M Fischer
Aug 30, 2011·British Journal of Pharmacology·Eric L Moore, Christopher A Salvatore
Feb 22, 2013·British Journal of Pharmacology·C S Walker, D L Hay
May 2, 2015·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·T R GlowkaS Wehner
Nov 6, 2018·Headache·Frederick R Taylor
Jan 13, 2010·The Journal of Pharmacology and Experimental Therapeutics·Christopher A SalvatoreStefanie A Kane
Jun 3, 2021·British Journal of Pharmacology·Michael L GareljaDebbie L Hay

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Methods Mentioned

BETA
glycosylation
transfection

Software Mentioned

GraphPad PRISM

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