Novel Macrocyclic Antagonists of the Calcitonin Gene-Related Peptide Receptor: Design, Realization, and Structural Characterization of Protein-Ligand Complexes

ACS Chem Neurosci. 2022 Mar 16;13(6):751-765. doi: 10.1021/acschemneuro.1c00696. Epub 2022 Mar 4.

Abstract

A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 (1) and HTL0028125 (2), is described. Structural characterization by X-ray crystallography of the interaction of two of the macrocycle antagonists with the CGRP receptor ectodomain is described, along with structure-activity relationships associated with point changes to the macrocyclic antagonists. The identification of non-peptidic/natural product-derived, macrocyclic ligands for a G protein coupled receptor (GPCR) is noteworthy.

Keywords: CGRP; CGRPR; GPCR; antagonist; macrocycle; macrocyclic.

MeSH terms

  • Calcitonin Receptor-Like Protein / chemistry
  • Calcitonin Receptor-Like Protein / metabolism
  • Crystallography, X-Ray
  • Ligands
  • Receptors, Calcitonin Gene-Related Peptide* / chemistry
  • Receptors, Calcitonin Gene-Related Peptide* / metabolism
  • Receptors, G-Protein-Coupled* / metabolism

Substances

  • Calcitonin Receptor-Like Protein
  • Ligands
  • Receptors, Calcitonin Gene-Related Peptide
  • Receptors, G-Protein-Coupled