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

Obesity leads to disruption of the functioning of the human body and an increase in the prevalence of various chronic diseases and mortality (Zięba 2007). Obese individuals are more likely to suffer from cardiovascular diseases (ischemic heart disease, hypertension, diabetes, and diseases of the digestive system) and they are at higher risk of developing colorectal, gallbladder, pancreas and kidney cancers. Treatment of obesity is very difficult and expensive. Development of additional diseases due to obesity also generates huge costs of treatment (World Obesity Federation 2014). Therefore, the search for compounds that effectively help reduce weight and show low risk for potential side effects is extremely important for the general public.

Oral administration to rats of LuAE58054 potently inhibited striatal in-vivo binding of the 5-HT₆ antagonist radioligand [³H]LuAE60157, with an ED₅₀ of 2.7 mg/kg. Steady-state modeling of an acute pharmacokinetic/5-HT₆ receptor occupancy time-course experiment indicated a plasma EC₅₀ value of 20 ng/ml. Administration of LuAE58054 in a dose range (5–20 mg/kg p.o.) led to more than 65 % striatal 5-HT₆ receptor binding occupancy in vivo. These results indicate that LuAE58054 is a selective antagonist of 5-HT₆ (Arnt et al. 2010).

Research into the influence of LuAE58054 (idalopirdine) on body weight in animals with diet-induced obesity was performed by intraperitoneal injection of 5 mg kg⁻¹ bw of the compound for 21 days. This dose was the lowest effective dose in a rat model of cognitive impairment (Arnt et al. 2010). Intraperitoneal injection was chosen as an administration route to ensure that the high-fat diet did not influence the compound absorption. This route of administration has also been used in research into the influence on body weight of another 5-HT₆ receptor antagonist - PRX-07034 - in a similar model of high-fat diet-induced obesity (Heal et al. 2008).

In safety and efficacy studies with idalopirdine in patients with moderate Alzheimer’s disease, this compound reduced body weight only in 5 % of patients, and this effect was not significant (Wilkinson et al. 2014). However, there was a notable difference between the elderly people who were the focus of the research and a population of obese people. Changes in body weight can affect the overall health of elderly patients and should not occur in these individuals. In particular, weight loss can lead to many health complications affecting daily activities, loss of functional status and mortality. Even looking for drugs that increase body weight in these people (Hilas and Avena-Woods 2014).

Our research has been conducted on the model of obesity. The research clearly showed a significant reduction of body fat and triglycerides in animals which were disrupted in these parameters – obesity model. This is the first report showing that idalopirdine has therapeutic potential against obesity.

Obesity is a major cause of insulin resistance, impaired glucose tolerance, type II diabetes, elevated plasma concentrations of triglycerides and low density cholesterol and decreased plasma concentrations of high density cholesterol and hypertension (Mokdad et al. 2001; Pi-Sunyer 2002). It is important, therefore, that in animals treated with LuAE58054 an anorectic effect occurred in parallel with lower plasma triglyceride levels compared to those in the obese control animals. After 21 days of treatment with Lu AE58054 the fat pads in peritoneal tissues of the rats were weighed and decreases in visceral fat depots were observed. Idalopirdine also caused a statistically significant reduction in visceral fat depots in rats without induced obesity. This is interesting, because there was no weight loss in rats fed standard feed treated with idalopirdine. Additional studies are, therefore, needed to determine why this occurred and what its cause was.

The present studies indicated that the reduction in food intake in obese animals during administration of LuAE58054 is associated with a reduction in their weight. This is consistent with the observations of many researchers who assert that the anorexic effect of 5-HT₆ ligands is associated with reduced food intake via a mechanism that is consistent with an enhancement of satiety (Heal et al. 2008).

Administration of Lu resulted in statistically significant changes in water intake in different weeks of treatment. In the first week, a statistically significant increase in water consumption was observed compared to the intake of the control group. It is assumed that increased intake of water can reduce food intake (Muckelbauer et al. 2013). Those rats fed a high fat meal take less water than rats fed a standard feed (data not shown), which may be related to the fact that a high-fat feed in the form of a paste is not as dry as the standard feed. To understand why it is that in the second and third week a decline in the uptake of water is observed, it is necessary to look for the cause. In the literature there are no reports focusing on the effect of 5-HT₆ ligands on water consumption, apart from the impact on water intake in a free-drinking test, where the SB-258585 – antagonist of these receptors did not affect the intake of water after a single administration (Wesołowska et al. 2007). It is known that the stimulation of 5HT_1A or 5-HT_1B receptors leads to a decrease in water consumption (Clissold et al. 2013). Increasing the water intake by animals can be associated with activation of metabolic processes, such as increases in both fatty acid oxidation and energy expenditure (Jbilo et al. 2005; Liu et al. 2005). The increase in drinking may be related to an increase in thermogenesis, as in studies with sibutramine administration in animals (Connoley et al. 1999; Skill et al. 2000). In the literature, there are other studies where sibutramina does not affect the level of water intake in rat models of diet-induced obesity (Pratt and Connolly 2010). Further detailed studies are needed to confirm the effect of idalopirdine and other serotonin receptor ligands on water consumption, and to ascertain whether this is linked with the effect of decreasing body weight.

Disorders of spontaneous activity (significant increase in activity as well as sedation) and the stress induced by the test compound could be very disadvantageous and could disturb an impact assessment of the test compound on body weight. This study demonstrated that repeated administration of Lu AE58054 to obese rats did not induce stress. It was essential to house animals in pairs in home cages. The test compound does not cause sedation. Therefore, the observed anorectic effect was definitely not associated with a reduction in the spontaneous activity of animals.

The anorectic effect of Lu AE58054 in the model of obesity where the animals were treated with high-fat feed ad libitum (DIO) was comparable to the anorectic effects of other 5-HT₆ receptor ligands. In this model of obesity, 5 weeks of intraperitoneal treatment with PRX-07034 at the dose of 10 mg kg⁻¹ bw/day caused a moderate decrease in rats’ food consumption and weight-loss (Heal et al. 2008). BVT 5182 – the other antagonist of the 5-HT₆ receptor – was also shown to produce a reduction in food intake and body weight in DIO rats, simultaneous with decreases in visceral adiposity. This compound has presented anorectic activity in DIO mice and ob/ob mice too, when administered subcutaneously at a dose of 3 mg kg⁻¹ bw (Heal et al. 2008). Ro 04–6790 at a high dose of 30 mg kg⁻¹ i.p. also significantly attenuates body weight-gain in growing rats when given daily for 3 days (Woolley et al. 2001). E6837 – a partial agonist of the 5-HT₆ receptor - when administered intragastrically at a dose of 30 mg kg⁻¹ bw twice a day for 30 days reduces weight and food intake (Fisas et al. 2006). A comparison of the anorectic effects of Lu AE58054 and the mentioned ligands is presented in Table 2.

The anorexic effect of Lu AE58054 shown in this study was also comparable to that of sibutramine which, when administered intragastrically for 21 days at a dose of 3 mg kg⁻¹ bw/day to high-fat-fed obese rats, reduced their body weight by 10 % (Brown et al. 2001); while when administered at a dose of 5 mg kg⁻¹ bw day for 28 days resulted in weight loss of 10.8 % (Fisas et al. 2006), and at a dose of 7.5 mg kg⁻¹ bw/day for 28 days reduced body weight by 7.6 % (Hansen et al. 2010).

The proportion of patients achieving weight loss of at least 5 % ranges from 37 to 47 % for lorcaserin, 35 to 73 % for orlistat, and 67 to 70 % for top-dose phentermine plus topiramate–extended release. The safety and efficacy of these drugs have been determined for short-term use and there is limited data for their long-term use (Yanovski and Yanovski 2014). These data emphasize the need for drugs with different mechanisms of action, with improved efficacy and greater safety potential. 5-HT₆ receptor antagonists do not cause disturbances in the cardiovascular system (Heal et al. 2008); therefore, the search for drugs against obesity in this group of drugs is particularly advantageous and important.