ABSTRACT
Melanocortins mediate the effects of leptin in the central nervous system (CNS) and regulate energy balance through the MCR3 and MCR4 receptors. Here, we examined the specific role of MCR4 in modulating fat consumption. In a three-choice feeding model, the non-selective melanocortin agonist MT-II decreased fat consumption preferentially and the effect was absent in mice deficient in MCR4. Further, an agonist selective for the MCR4 subtype [Danho W, Swistok J, Cheung A, Chu XJ, Wang Y, Chen L, et al. Highly selective cyclic peptides for the melanocortin-4 receptor: design, synthesis, bioactive conformation and pharmacological evaluation as anti-obesity agents. In: Lebl M, Houghten R, editors. Peptides: the wave of the future. Am. Peptide Soc., 2001. p. 701-703.] also decreased dietary fat intake in a MCR4-dependent manner. Thus, MCR4 activation is both necessary and sufficient for the control of dietary fat intake by melanocortin signals and may provide a pharmacological means to control the consumption of fatty foods.
Subject(s)
Eating/physiology , Energy Intake/physiology , Receptor, Melanocortin, Type 4/physiology , alpha-MSH/analogs & derivatives , Animals , Body Weight/drug effects , Body Weight/physiology , Dietary Fats/administration & dosage , Dose-Response Relationship, Drug , Eating/drug effects , Energy Intake/drug effects , Feeding Behavior , Female , Food Preferences/drug effects , Food Preferences/physiology , Humans , Male , Mice , Mice, Inbred C57BL , Mutation , Peptides, Cyclic/pharmacology , Receptor, Melanocortin, Type 4/agonists , Receptor, Melanocortin, Type 4/genetics , alpha-MSH/pharmacologyABSTRACT
An imidazolylpyrimidine was identified in a CXCR2 chemokine receptor antagonist screen and was optimized for potency, in vitro metabolic stability, and oral bioavailability. It was found that subtle structural modification within the series affected the oral bioavailability. Potent and orally available CXCR2 antagonists are herein reported.