4-oxo-1,4-dihydrocinnoline Derivative with Phosphatase 1B Inhibitor Activity Enhances Leptin Signal Transduction in Hypothalamic Neurons

Abstract

Most of regulatory effects of leptin on feeding behavior and energy metabolism are implemented via the hypothalamic leptin system. Attenuation of its activity leads to hyperphagia, obesity and other metabolic disorders. To prevent these pathological conditions, it is necessary to develop approaches aimed at restoring the leptin system. Most promising of them is creating efficient inhibitors of protein phosphotyrosine phosphatase PTP1B, a negative regulator of leptin signaling. The aim of this work was to synthesize a new compound, ethyl-3-(hydroxymethyl)-4-oxo-1,4-dihydrocinnoline-6-carboxylate (PI-04), a 4-oxo-1,4-dihydrocinnoline derivative with a PTP1B inhibitor activity, and to study its effect on IRS2- and STAT3-dependent leptin pathways in culture of hypothalamic neurons isolated from 18-day-old rat embryos. It was shown that PI-04 enhances the stimulatory effect of leptin on phosphorylation of the IRS2 protein at the Ser⁷³¹ residue and of the STAT3 transcriptional factor at the Tyr⁷⁰⁵ residue, suggesting a potentiation of functional responses of hypothalamic neurons to leptin in the presence of this compound. The potentiating effect of PI-04 on leptin signaling was implemented at micromolar concentrations when this substance had virtually no effect on neuronal survival. The data obtained are promising in terms of creating phosphatase PTP1B inhibitors based on 4-oxo-1,4-dihydrocinnoline, as well as the possibility of their further use to prevent and correct metabolic disorders caused by attenuated activity of the hypothalamic leptin system.