High-affinity, potent and selective melanocortin receptor 4 (MC-4R, MC4-R, MC4R) agonist with in vivo efficacy in a chronic rat food intake and body weight model.
LY2112688 is a beta-melanocyte-stimulating hormone (β-MSH)-derived peptide that acts as a high-affinity, potent and selective melanocortin receptor 4 (MC-4, MC-4R, MC4-R, MC4R) agonist (human/rat MC-4 Ki = 0.55/0.39 nM; human MC-1/3/5 Ki = 16.78/56.79/>500 nM). LY2112688 selectively induces MC-4-mediated cAMP release (MC-4/3 EC50 = 0.25 nM/1.61 nM, MC-4/3 Emax = 94.5%/84.1% of NDP-α-MSH Emax using HEK293 expressing respective human receptors) and exhibits in vivo efficacy in reducing daily food intake and promoting weight loss among diet-induced obese rats (75 & 299 nmol/kg/day s.c.).
Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of
The New England journal of medicine, 360(1), 44-52 (2008-12-19)
Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated in the control of energy balance and blood pressure in rodents, but there is no information regarding such an association
The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of body weight homeostasis. Activation of MC4R causes dramatic weight loss in rodent models, and mutations in human are associated with obesity. This makes MC4R a logical target for
The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor expressed in the brain, where it controls energy balance through pathways including α-melanocyte-stimulating hormone (α-MSH)-dependent signaling. We have reported that the MC4R can exist in an active conformation that signals constitutively
The central melanocortin system is broadly involved in the regulation of mammalian nutrient utilization. However, the function of melanocortin receptors (MCRs) expressed directly in peripheral metabolic tissues is still unclear. The objective of this study was to investigate the lipolytic
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