Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist

Abstract

ARTICLESMelanin-concentrating hormone (MCH), a cyclic 19-aminoacid polypeptide, is produced predominantly by neurons in the lateral hypothalamus and zona incerta which project broadly throughout the brain 1 . Several lines of evidence implicate MCH as an important mediator in the regulation of energy balance and body weight. Central MCH administration stimulates food intake while fasting results in an increase in MCH expression 2 . Mice lacking the gene encoding MCH are lean, hypophagic and maintain elevated metabolic rates 3 . In contrast, mice overexpressing the MCH gene are susceptible to obesity and insulin resistance 4 . Although these findings support a rationale for MCH antagonists in the treatment of obesity, it is unclear if sufficient MCH tone exists to produce a robust and sustained loss of body weight after chronic MCH-receptor blockade. Moreover, because genetic manipulation of the MCH gene also affects the expression of neuropeptide E-I and neuropeptide G-E, which are processed from the same prehormone precursor as MCH, the observed phenotypes may be influenced by changes in the levels of these less characterized peptides 5 . The effects of MCH are mediated through receptors in the rhodopsin superfamily of G protein-coupled receptors (GPCRs). MCH1 receptor (MCH1-R) has been isolated from rodents and humans 6,7 , whereas MCH2-R has thus far been identified only in humans 8,9 . To assess the role of MCH1-R, we identified a selective, high-affinity MCH1-R antagonist and evaluated it in several animal models. We report here that the acute administration of a MCH1-R antagonist attenuated central MCH-stimulated food intake, and reduced consumption of palatable food. Moreover, chronic administration of this antagonist produced a robust and sustained decrease in body weight in rats with diet-induced obesity. As the distribution of MCH1-R binding sites in the central nervous system (CNS) is suggestive of a role for MCH in the regulation of mood and stress, we tested the MCH1-R antagonist in several animal models of depression and anxiety. Pharmacological blockade of the MCH1-R produced a profile similar to clinically used antidepressants and anxiolytics, suggesting that the MCH1-R might be a novel target for the treatment of depression and anxiety. SNAP-7941 is a selective, high-affinity MCH1-R antagonistScreening of our GPCR-biased compound collection against the human MCH1-R in a functional assay measuring intracellular Ca 2+ mobilization resulted in the discovery of a highpotency antagonist, SNAP-7941,4-tetrahydro-5-pyrimidinecarboxylate hydrochloride) (Fig. 1a). SNAP-7941 is a competitive antagonist of MCH in a [3 H]phosphoinositide accumulation assay in a mammalian cell line expressing the human MCH1-R (Fig. 1b). The Schild regression from these data estimated a pA 2 of 9.24 with a slope of 0.98 (r 2 = 0.94) for SNAP-7941 (Fig. 1b, inset), which predicts a K b of 0.57 nM. This compound was greater than 1,000-fold selective for MCH1-R compared with the human MCH2-R, as well as GPCRs associated with food...

Physiological arousal: a role for hypothalamic systems

“…At the cellular level, glucose dosedependently enhances the electrical excitability of MCH neurons by inducing depolarization and increasing membrane resistance, but has the opposite effect on the electrical activity of Hcrt cells [83]. As a result of this participation in food intake behavior and energy homeostasis, a plethora of MCHR1 antagonists have been developed in recent years [137,138]. In contrast to the Hcrt system, MCH neurons are not activated during acute and chronic morphine treatment, or following naltrexone-induced withdrawal [122,139].…”

Human Th2 cells selectively express the orexigenic peptide, pro-melanin-concentrating hormone

“…MCHR2 is not present in the rodent genomes, but orthologs have been identified in ferret, dog and rhesus monkey, in addition to the human gene (24). PMCH therefore has an important role in increasing appetite (25), and a small molecule antagonist of MCHR1 has been shown to reduce feeding and weight gain in rats fed a high fat diet ad libitum (26).…”

MCH-R1 Antagonists as Potential Anti-obesity Drugs. Design Strategies and Structure-activity Relationship

“…Similarly, specific MCH-R1 antagonists produced comparable effects. 26 Recently, results of Karlsson et al supported an involvement of the MCH system in the regulation of energy balance as well as addiction-like behaviors such as sucrose reward and seeking. Data show that MCH-R1 antagonists decreased operant responding for sucrose but not saccharin, and reduced food intake more than sucrose, suggesting that MCH system may play a stronger role in caloric rather than reward processes.…”