The long-term goal of this work is to advance the development of novel antinociceptive agents by increasing our understanding of receptors that facilitate responses to tissue injury and inflammation. Neuropeptides released from sensory fibers contribute to the hyperalgesia of sensory neurons by modulating responses of nerve fibers and promoting local edema via direct vasodilatation. The neuromodulator, calcitonin gene-related peptide (CGRP) is released from peripheral and central nerve terminals upon sensory activation. Furthermore, CGRP activated receptors have been shown to cause dilation of cerebral arterioles and to modify opiate effects in humans. However, the bioavailability and protease resistance of receptor ligands limits exploitation of CGRPs nociceptive effects. Lead compounds may be identified from modifications of the endogenous peptide and by assessment of extant pharmaceutical drug repositories or synthetic combinatorial libraries, using conventional drug screening techniques. Alternatively, ligands may be logically designed on the basis of reliable structure information of the receptor complexed with CGRP. This proposal focuses on structural characterization of the CGRP receptor using biochemical, molecular biological and cell biological approaches. This research is guided by the hypothesis that detailed insights into the molecular mechanisms of ligand dependent activation will provide information for rational development of CGRP receptor active drugs.
Aim one will investigate the hypothesis that the N-terminus domain of the receptor is a major source of binding contacts for the endogenous peptide agonist.
Aim two will test the hypothesis that an agonist-mediated release of an intermolecular constraint is an initial process of CGRP receptor activation. From these aims a preiiminary molecular model of the activated CGRP receptor-binding pocket can be proposed. The information derived from this research will advance our understanding of the molecular events that occur during I cellular signaling by the CGRP receptor system as well as potentially identitying novel ligands that may be effective in modifying neurogenic inflammation and the hyperalgesia of nociception. ? ? ?
