5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.

By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence supporting this notion is based on several findings: (i) a highly selective nonpeptide MC4R agonist augments erectile activity initiated by electrical stimulation of the cavernous nerve in wild-type but not Mc4r-null mice; (ii) copulatory behavior is enhanced by administration of a selective MC4R agonist and is diminished in mice lacking Mc4r; (iii) reverse transcription (RT)-PCR and non-PCR based methods demonstrate MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and (iv) in situ hybridization of glans tissue from the human and rat penis reveal MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicate the MC4R in the modulation of penile erectile function and provide evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. Our results provide a basis for the existence of MC4R-controlled neuronal pathways that control sexual function.O ur understanding of the physiology and anatomy of erectile function has advanced considerably in recent years (1-4). Penile erection is a highly coordinated reflex that is subject to modulation at many levels of the neuraxis. Relaxation of smooth muscle fibers of erectile tissue and concomitant dilatation of the arterial supply in the penis produce penile erection. Activation of neurons in the sacral spinal cord triggers activity in the pelvic nerve and, subsequently, the cavernous nerve, which can lead to the release of mediators of vasorelaxation, including nitric oxide. These mediators modulate cyclic nucleotide levels resulting in Ca 2ϩ sequestration and relaxation of smooth muscle fibers of the corpora cavernosa and corpus spongiosum in the shaft of the penis to produce arterial dilatation, engorgement of the penis with blood, and tumescence. Erections can be triggered either by peripheral (tactile) or by central (visual, olfactory, auditory, or imaginative cues) activation of somatic pathways and, as such, are influenced by tonic and phasic activity in the lumbosacral spinal cord and the brain.Five melanocortin heterotrimeric GTP-binding protein (G protein)-coupled receptors have been identified as expressed in different tissues (5, 6). The functional role of each of these five melanocortin receptors is being defined. Rodent and human genetic and pharmacological evidence indicates that activation of melanocortin 4 receptor (MC4R) results in a lean phenotype, whereas inactivation of the MC4R results in obesity (7-10). Recent studies have demonstrated that MTII, a cyclic analogue of ␣-mel...

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.

Bombesin receptor subtype-3 (BRS-3) is an orphan G proteincoupled receptor implicated in the regulation of energy homeostasis. Here, we report the biologic effects of a highly optimized BRS-3 agonist, ( -5046). Single oral doses of MK-5046 inhibited 2-h and overnight food intake and increased fasting metabolic rate in wild-type but not Brs3 knockout mice. Upon dosing for 14 days, MK-5046 at 25 mg ⅐ kg Ϫ1 ⅐ day Ϫ1reduced body weight of diet-induced obese mouse by 9% compared with vehicle-dosed controls. In mice, 50% brain receptor occupancy was achieved at a plasma concentration of 0.34 Ϯ 0.23 M. With chronic dosing, effects on metabolic rate, rather than food intake, seem to be the predominant mechanism for weight reduction by MK-5046. The compound also effectively reduced body weight in rats and caused modest increases in body temperature, heart rate, and blood pressure. These latter effects on temperature, heart rate, and blood pressure were transient in nature and desensitized with continued dosing. MK-5046 is the first BRS-3 agonist with properties suitable for use in larger mammals. In dogs, MK-5046 treatment produced statistically significant and persistent weight loss, which was initially accompanied by increases in body temperature and heart rate that abated with continued dosing. Our results demonstrate antiobesity efficacy for MK-5046 in rodents and dogs and further support BRS-3 agonism as a new approach to the treatment of obesity.

No abstract

No abstract

AMP-activated protein kinase (AMPK)-mediated cellular metabolic responses to tissue-specific and whole-body stimuli play a vital role in the control of energy homeostasis. As a cellular energy-sensing mechanism, AMPK activation stimulates glucose uptake and fat oxidation, while it suppresses lipogenesis and gluconeogenesis. The cumulative effects of AMPK activation lead to beneficial metabolic states in liver, muscle and other peripheral tissues that are critical in the pathogenesis of obesity, type 2 diabetes and related metabolic disorders. Activators of AMPK that target selected tissues hold potential as novel therapeutics for diseases in which altered energy metabolism contributes to aetiology.

We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.