New Opportunity for Serotonin Receptor Agonists

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Nature Reviews Drug Discovery | AOP, published online 14 December 2007; doi:10.1038/nrd2492

M E TA B O L I C D I S E A S E New opportunity for serotonin receptor agonists

With type 2 diabetes prevalence Serotonin (5-hydroxytryptamine; Next, the authors set out to investi increasing at an alarming rate, there 5-HT) plays important roles as a gate the mechanism of action of these

is a growing need for novel treat neurotransmitter in the CNS and as a agents and observed that 5-HT2C ments. Recent work suggests that mediator of peripheral signals. It acts receptor activation stimulated central central neural pathways may have on members of the seven 5-HT recep melanocortin pathways, an action an important role in glucose homeo tor families to exert various actions, known to enhance insulin sensitivity.

stasis, with such pathways having including the regulation of anxiety, In ob/ob mice, 1 week of 5-HT2C the potential to be therapeutically body temperature, mood, sleep and receptor agonist treatment increased modulated. Now, writing in Cell appetite. Pharmacological modulators levels of pro-opiomelanocortin Metabolism, Heisler and colleagues of specific 5-HT receptor isoforms — the precursor of the endogenous show that serotonin 2C receptor ago have been developed to treat various melanocortin agonist, α-melanocyte- nists can improve glucose tolerance conditions that are associated with stimulating hormone (α-MSH) — in and reduce plasma insulin levels. these actions, including exploitation the arcuate nucleus of the hypothala This suggests that pharmacological of the anorectic effect following cen mus. Pharmacological melanocortin

modulation of serotonin receptor tral 5-HT2C receptor activation for the receptor (MCR) blockade and MCR- activity may be an effective new treatment of obesity. In mice, deletion knockout mouse models revealed the

approach to treat type 2 diabetes. of 5-HT2C receptors leads to insulin subsequent increased level of α-MSH resistance and type 2 diabetes, but improves glucose clearance by the possibility of receptor activation stimulating melanocortin 4 receptors for treatment of this disease is largely (MC4R); enhancing activity of sym unexplored. pathetic preganglionic neurons in Therefore, to determine whether the intermediolateral nucleus of the

5-HT2C receptor stimulation could spinal cord. These MC4R-dependent have beneficial effects on glucose effects occurred in association with homeostasis, the authors treated decreased plasma insulin levels, insulin-resistant mouse models with improved glucose tolerance, and

specific 5-HT2C receptor agonists. increased insulin signalling in the Diet-induced obese mice and leptin- muscle and liver. deficient Lepob (ob/ob) mice treated for The identification of improvements

2 weeks with 5-HT2C receptor agonists, in glucose homeostasis following

such as m-chlorophenylpiperazine, 5-HT2C receptor activation illustrates exhibited a dramatic 50% reduction in a new mechanistic strategy to treat plasma insulin levels in both models. type 2 diabetes, highlighting a novel Importantly, this was without effects therapeutic application for a class of on blood glucose, food intake, activity compounds developed years ago. or body mass at the doses used in the Sarah Crunkhorn study. Pharmacological blockade of

5-HT2C receptors abolished effects on ORIGINAL RESEARCH PAPER Zhou, L. et al. glucose tolerance, verifying that these Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling effects were directly mediated by pathways. Cell Metab. 6, 398–405 (2007)

5-HT2C receptors.