Idalopirdine - a small molecule antagonist of 5-HT6 with therapeutic potential against obesity.

Magdalena Dudek,Marcin Kołaczkowski,Monika Marcinkowska,Adrian Olczyk,Adam Bucki

doi:10.1007/s11011-015-9736-3

Magdalena Dudek, Marcin Kołaczkowski + Show 3 more

Open Access

https://doi.org/10.1007/s11011-015-9736-3

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Abstract

5HT6 receptor antagonists offer the potential for safe and effective drugs against obesity, because they can reduce weight without causing serious side effects in the cardiovascular system. Also, their anorexic effect is associated with reduced food intake via an enhancement of satiety. In the present study we investigated the anorexic effect of idalopirdine (LuAE58054) in a model of obesity induced by high-fat diet. To induce obesity in rats, the animals were treated with feed with a fat content of 40 %. Body weight was controlled and the amount of food and water consumed was determined. The influence of the test compound on the lipid profile and glucose level was measured, as well as locomotor activity in home cages on the 20th day of the treatment. LuAE58054, at 5 mg kg−1/day i.p., was significantly anorectic in this model of obesity. Animals treated with LuAE58054 weighed 8 and 9.2 % less than the control obese animals on the 12th and 21st days, respectively. It significantly reduced food intake and the amount of peritoneal fat in animals, and reduced the level of triglycerides in plasma. LuAE58054 did not have a statistically significant effect on the spontaneous activity of diet-induced obese rats. The present study clearly demonstrates the effectiveness of LuAE58054 in reducing body weight. This compound is in phase III of clinical trials for the treatment of cognitive deficits associated with Alzheimer’s disease and schizophrenia. It is a 5HT6 receptor antagonist and is, therefore, free of those unacceptable side effects that preclude chronic use of anti-obesity drugs with other mechanisms of action. The search for an effective and safe anti-obesity drug is essential for an increasingly obese population; therefore, the anorectic action of LuAE58054 is important and there is a need for more research in this direction.

Highlights

Obesity is a serious problem in many countries
Acute administration of serotonergic compounds alters the expression of peptidergic appetitive effectors within the hypothalamus, namely it causes an increase in anorectic proopiomelanocortin mRNA and a decrease in orexigenic neuropeptide Y mRNA (Choi et al 2006)
It is believed that 5-HT6 receptor antagonists block the serotonin-dependent activation of GABA neurons, which results in reduction of inhibitory effects of GABA on pro-opiomelanocortin neurons in the arcuate nucleus with subsequent inhibition of the hunger signal induction (Sargent and Henderson 2011)

Summary

Introduction

The World Health Organization estimates that it affects between 30 and 80 % of adults and up to 30 % of children, and effective treatment of this disease is one of the major health problems of the 21st century. GABAergic neurons have an inhibitory effect on the activity of proopiomelanocortin neurons in the arcuate nucleus, which induces a hunger signal in the hypothalamus. It is believed that 5-HT6 receptor antagonists block the serotonin-dependent activation of GABA neurons, which results in reduction of inhibitory effects of GABA on pro-opiomelanocortin neurons in the arcuate nucleus with subsequent inhibition of the hunger signal induction (Sargent and Henderson 2011)

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