Mc4r Antagonists

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The development of selective, high affinity antagonists for MC4R trailed the development of MC4R agonists. Several structure-activity studies were reported on the lactam SHU9119, an analog of aMSH and a nonselective MC3R/MC4R antagonist (75,76). Analogs of SHU9119 with altered lactam ring sizes, amino acid substitutions and/or chirality changes in the "active core" were prepared in an effort to optimize receptor subtype selectivity (77-79). Replacement of His6 with 1-amino-1-cyclopentane carboxylic acid resulted in an hMC4R antagonist with improved selectivity against hMC3R (78). All other compounds displayed slightly lower or similar antagonistic activities to SHU9119 at the human or mouse MC4R with little improvement in selectivity over other receptor subtypes.

Recognition that Ac-Nle4 and His6 only minimally affect the binding of SHU9119 to hMC4R led to the design of smaller cyclic peptides which were selective and potent antagonists for the human hMC4R (76). Compound MBP10 (14). bearing a succinyl moiety in place of Asp5, displayed about 125-fold higher antagonist selectivity for hMC4R than hMC3R. This peptide did not activate hMCIbR, hMC3R and hMC4R even at micromolar concentrations and was only a weak agonist at hMC5R (EC5o=530 nM). Analogs of 14 with a glutaryl or o-phthalic group in place of the succinyl linker were recently reported to be less selective and less effective MC4R antagonists (35).

Several cyclic disulfide analogs of aMSH with ring sizes greater than 25 have been shown to be selective and effective antagonists at MC4R (80,81). HS014, Ac-cyclo(Cys-Glu-His-D-Nal(2')-Arg-Trp-Gly-Cys)-Pro-Pro-Lys-Asp-NH2, is an antagonist at MC4R (20-fold selective over MC3R) and a partial agonist at MC1R and MC5R. HS024, with a larger ring size, Ac-cyclo(Cys-Nle-Arg-His-D-Nal(2')-Arg-Trp-Gly-Cys)-NH2, did not activate MC1R, MC3R , MC4R or MC5R, and its affinity for MC4R was about 70-, 20- and 10-fold higher than for MC1R, MC3R and MC5R, respectively. These peptides stimulated feeding in rodents after i.c.v. injection. The latest MC4R antagonist from the same group is HS131, Ac-cyclo(Cys-Gly-D-Nal(2')-Arg-Trp-Cys)-NH2. This antagonist increased food intake in rodents after i.c.v. and s.c. administration (82).

The tetrapeptide, Ac-His6-D-Nal(2')7-Arg8-Trp9-NH2, which comprises the "active core" of a-MSH, but with D-Nal(2') in place of Phe7, was found to be a moderately effective antagonist at the mouse MC4R with Ki of 17 nM (28). Its elongated analog (Ro27-4680), CH3CH2CH2CO-His6-D-Nal(2')7-Arg8-Trp9-Sar10-NH2 is a weak partial agonist at MC4R, can antagonize NDP-a-MSH activation at high concentrations, and can increase food intake in rodents when administered centrally (25).

Anxiolytic-like and antidepressant-like activities were reported for MCL0129 (15), representing the first nonpeptide MC4R antagonist published (83). This compound inhibited [125I]NDP-aMSH binding to the cloned human MC4R with high affinity and showed no affinity for the human MC1bR and rat MC3R even at a concentration of 10 nM.

Other patent applications have been published on the preparation and use of benzylideneamino guanidines and aromatic amides (as MC1R and MC4R selective agonists and/or antagonists) for the treatment of diseases related to the melanocortin receptors (68,70,71,84).

Conclusion - Significant progress has been made in the past several years in the development of selective MC4R modulators. In particular, the discovery of small molecule agonists and antagonists will provide the necessary tools to further explore the utilities of these ligands in the treatment of various pathological conditions, including obesity, erectile dysfunction, inflammatory diseases and CNS diseases. Furthermore, these selective tools will allow in-depth evaluation of the melanocortin system and the delineation of the functional roles of different MC receptor subtypes.

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Chapter 5. Secretase Inhibitors for Alzheimer's Disease

Anna Y. Kornilova and Michael S. Wolfe Center for Neurologic Diseases Brigham and Women's Hospital and Harvard Medical School 77 Avenue Louis Pasteur, Boston, MA 02115

Introduction - Brain deposits of the amyioid-p peptide (Ap) in the form of plaques are a hallmark of Alzheimer's disease (AD), and formation and aggregation of this peptide are strongly implicated in the etiology of the disease (1). Ap is produced from the amyloid p-protein precursor (APP), a single-pass membrane protein of unknown function, by the sequential action of two proteases, p- and y-secretases, as depicted in Figure 1 (2). Proteolysis by p-secretase leads to release of the large extracellular/luminal domain of APP, and the 99-residue C-terminal fragment that remains (C99) is then proteolyzed within its transmembrane domain by y-secretase, producing a heterogeneous collection of Ap peptides ranging from 38 to 43 residues long. Although the 42-residue version (Ap42) is a minor species, this peptide is particularly prone to self-assembly into fibrils and is the major Ap isoform found in AD plaques (3-4).

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