The long term objective of this research is to develop small molecule antagonists of the melanocortin-4 receptor (MC4-R) as therapeutic agents for the treatment of cachexia. MC4-R antagonists are expected to stimulate feeding and to increase lean body mass. Further there is evidence from murine animal models that blockade of the MC4-R results in amelioration of cachexia resulting from the action of induced cytokines. MC4-R antagonists may serve as therapeutic agents for cachexia associated with cancer or AIDS. Weight loss in senescent adults, including those suffering from Alzheimer's disease, may also be amenable to treatment with MC4-R antagonists.
The specific aims for phase I are to develop high affinity small molecule antagonist ligands (Ki less than 10 nM) for MC4-R and to develop predictive MC4-R pharmacophore models for antagonist activity. Computational methods will be used to optimize MC4-R antagonist activity in an iterative library design approach. Non-peptide small molecule antagonist leads (Ki about 100-300 nM) have been discovered and these leads will be optimized by a combination of directed combinatorial chemistry, computer assisted compound design based on generation of predictive pharmacophore models, and the application of sound medicinal chemical expertise.
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| Nickolls, Sarah A; Cismowski, Mary I; Wang, Xiaochuan et al. (2003) Molecular determinants of melanocortin 4 receptor ligand binding and MC4/MC3 receptor selectivity. J Pharmacol Exp Ther 304:1217-27 |
| Foster, Alam C; Joppa, Margaret; Markison, Stacy et al. (2003) Body weight regulation by selective MC4 receptor agonists and antagonists. Ann N Y Acad Sci 994:103-10 |
