Discovery of Orexant and Anorexant Agents with Indazole Scaffold Endowed with Peripheral Antiedema Activity .

Background. In the last two decades, obesity has assumed the form of a pandemic, often related to the development of cardiovascular diseases (CVD) and strokes. There is a worldwide emergency that requires the development of novel and safer anti-obesity treatments. Rimonabant, a well-known inverse agonist of the type-1 cannabinoid receptor (CB1), associated with lifestyle modifications was successfully engaged in the control of obesity by reducing appetite and weight gain. Though this drug has shown to be effective to control body weight and to manage obesity, it has been withdrawn from the market due to its important side effects. Thus, a novel drug able to provide the same therapeutic efficacy without the dangerous side efficacy without the dangerous side effects is an urgent need. We report a series of lonidamine joined Leu, tert-Leu and Val amino acids with different C-terminal functional groups (LONI1-4,11, Figure 1) designed as hybrids of Fubinaca family compounds and Rimonabant, as novel compounds endowed with orexant/anorexant activity. Methods. We evaluated the orexant/anorexant activity of LONI1-4,11 in the feeding test using CD-1 male mice after intraperitoneal (i.p.) administration (10 mg/kg). For a LONI11 formalin test and a tail flick test after an administration by the subcutaneous (s.c.,30–100 μg/20 µL) and intracerebroventricular (i.c.v.,10 µg/10 μL) routes, respectively, were also carried out in mice to investigate the antinociceptive property at the central and peripheral levels. Furthermore, Zymosan-induced edema (s.c., 100 µg/20 μL) and hyperalgesia (s.c., 100 µg/20 μL) assays were also performed to estimate the anti-inflammatory activity of LONI11 in mice model. Results. We observed a significant orexant effect for LONI11 and an intense anorexant effect for LONI2 and LONI4 (Figure 2). LONI11 at the doses of 10 µg/10 μL and 100 µg/20 μL produced a slight antinociceptive effect after i.c.v. and s.c. injections, respectively, in tail flick test (Figure 3, left panel) and in formalin test (Figure 3, right panel). In zymosan-induced edema (Figure 4, left panel) and hyperalgesia (Figure 4, right panel), LONI11 reduced the percent of paw volume increase and paw latency after s.c. administration, also suggesting a possible peripheral anti-inflammatory activity. Conclusions. These results could be useful as a starting point to optimize the pharmacological properties of rimonabant/Fubinaca hybrids and to better understand the molecular mechanism below their biological profile. An understanding of all the neuroendocrine networks and their roles in the hypothalamus to regulate the feeding behaviour could lead to the development of novel and safer approaches to manage the main nutritional disorders.