Victor J. Hruby
University of Arizona USA
Title: Design of Novel, Selective and Bioavailable Ligands for Closely Related Receptors and Pharmacophores: Conformational and Topographical Considerations
Biography
Biography: Victor J. Hruby
Abstract
Proopiomelanocortin (POMC) is a primordial animal gene that produces many of the key hormones and neurotransmitters critical for survival and reproduction. It also is involved in many of our most common degenerative diseases. It produces several hormones and neurotransmitters, including α-MSH, β-MSH, γ-MSH, ACTH, β-endorphin, β-lipotropin, etc. that target 5 melanocortin receptors (MC1R, MC2R, MC3R, MC4R and MC5R) as well as 3 opioid receptors and others. In the case of the melanocortin receptors, MC1R, MC3R, MC4R and MC5R, α-MSH (or δ-MSH) is the primary hormone/neurotransmitter and a common pharmacophore –His-Phe-Arg-Trp- is involved in agonist activation of the 4 receptors. This raises difficult problems in ligand design of agonists and antagonists for these 4 receptors which are involved in many diseases, including pigmentary diseases, feeding behavior diseases, sexual dysfunction, melanoma cancer, heart disease and many others. We have obtained highly potent and selective agonists and antagonists for the receptors that are stable and bioavailable. This required a combination of conformational and topographical considerations in peptide and peptidomimetic design. Several examples of successful applications of these considerations will be presented. Supported in part by grants from the U.S. Public HealthService, the NationalInstitutes of Health, NIDDK and GM.