Characterization of the Brain Penetrant Neuropeptide Y Y2 Receptor Antagonist SF-11.

Abstract

This paper discusses the biological and three-dimensional molecular structure of the novel, nonpeptide Y2R antagonist, SF-11 [N-(4-ethoxyphenyl)-4-(hydroxydiphenylmethyl)-1-piperidinecarbothioamide]. Pharmacokinetic studies in a rat model indicated that, following intraperitoneal dosing, SF-11 crossed the blood-brain barrier and was able to penetrate the brain, making it a suitable tool for behavioral studies. We showed for the first time that SF-11 decreased the immobility time in the forced swim test (FST) after acute peripheral administration (10 and 20 mg/kg), indicating that it has antidepressant potential. Inhibitors of the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways blocked the anti-immobility effect of SF-11, suggesting that these pathways are involved in the antidepressant-like activity of SF-11 in the FST. The results of locomotor activity of rats indicate that the effects observed in the FST are specific and due to the antidepressant-like activity of SF-11. These findings provide further evidence for the antidepressant potential of Y2R antagonists. Also, the application of Fourier transform infrared absorption (FT-IR) and Raman spectroscopy (RS) methods combined with theoretical density functional theory (DFT) calculations allowed us to present the optimized spatial orientation of the investigated drug. Structural characterization of SF-11 based on vibrational spectroscopic data is of great importance and will aid in understanding its biological activity and pave the way for its development as a new antidepressant agent.