Malcolm J. Kavarana

Exploring the Stereostructural Requirements of Peptide Ligands for the Melanocortin Receptors

Abstract: The melanotropin peptides α‐MSH, γ‐MSH, and β‐MSH are believed to be the natural ligands for the four melanocortin receptors, MC1R, MC3R, MC4R, and MC5R. However, these peptides generally have low selectivity for these receptors. We report on some approaches to the development of selective agonists and antagonists peptide ligands for these receptors.

The Development of a Novel Highly Selective and Potent Agonist for Human Melanocortin 4 Receptor

α-, β-, and γ-MSH, along with adrenocorticotropic hormones form a group of endogenous neuropeptides that regulate several key biological functions via five melanocortin (MC1R-MC5R) seven transmembrane G-protein coupled receptors (GPCR). Recent studies have indicated that in humans, the MC4R plays an important role in controlling feeding behavior and energy homeostasis [1,2]. These studies have further shown that agonists at hMC4R promote a feeling of satiety, while antagonists induce feeding. Thus selective agonists at this receptor could find therapeutic applications as anti-obesity drugs. This work discusses the development of the first highly selective and potent agonist MK-1 (c[(O)C-CH2-CH2-C(O)-His6-D-Phe7-Arg8-Trp9-Lys10]-NH2), at the human MC4 receptor versus the other three hMCR’s (hMC1, hMC3 and hMC5) respectively.

Synthesis of Amino Acids with Novel Biophysical Properties

Amino acids with unique physical properties have been used to study the conformational interactions of peptides and proteins. Two such molecules are pyrenylalanine and ferro-cenylalkyl derivatives of amino acids. Pyrenylalanine has unique spectroscopic properties that can be exploited to understand conformations of peptides [1], Ferrocenylalkyl derivatives of amino acids combine the properties of ferrocene and amino acids to offer compounds that will intercalate with DNA and can be targeted towards cancerous cells [2]. This paper describes the synthesis of these compounds and presents preliminary data concerning the intercalation of the ferrocenylalkyl amino acids towards DNA.