James W. Baumgartner

Design of a new peptidomimetic agonist for the melanocortin receptors based on the solution structure of the peptide ligand, Ac-Nle-cyclo[Asp-Pro-dPhe-Arg-Trp-Lys]-NH2

The solution structure of a potent melanocortin receptor agonist, Ac-Nle-cyclo[Asp-Pro-DPhe-Arg-Trp-Lys]-NH(2) (1) was calculated using distance restraints determined from 1H NMR spectroscopy. Eight of the lowest energy conformations from this study were used to identify non-peptide cores that mimic the spatial arrangement of the critical tripeptide region, DPhe-Arg-Trp, found in 1. From these studies, compound 2a, containing the cis-cyclohexyl core, was identified as a functional agonist of the melanocortin-4 receptor (MC4R) with an IC(50) and EC(50) below 10 nM. Compound 2a also showed 36- and 7-fold selectivity over MC3R and MC1R, respectively, in the binding assays. Subtle changes in cyclohexane stereochemistry and removal of functional groups led to analogues with lower affinity for the MC receptors.

SAR of the novel neuropeptides orexin-A and B

Detailed functional evaluation and structure analysis of these Ox-A and Ox-B analogs are currently underway. Future analog design aims to identify peptides with greater selectivity ratios at the Ox-1R and Ox-2R receptors. We are also interested in identifying antagonists molecules to aid in understanding the novel pharmacologyassociated with these new receptors.