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.

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“…SF 11 is a piperidincarbothiamide, while the other structures were arylsulfamoylbenzoid, aryl-1,2,4-oxadiazol (like SF 31 ( Figure 8 [ 34 ]) or arylsulfonylmethylisoxazol. SF 11 evaluated further by Domin et al [ 104 ] showed a good uptake into the rat brain. The authors suggest, based on results of forced swimming tests in rats, an anti-depressant-like action of the compound.…”

“…SF11 and SF31 have a log P at 4.8, which might indicate a reduced selectivity of such compounds in regard to the NPY2 subtype. Test of SF 11 and SF31 for their affinity to classical GPCR receptors [ 104 ] showed for SF 31 relatively few interferences but for SF11 also interactions with 5HT receptors or dopamine transporters [ 104 ].…”

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“…However, clinically, we found that the neurotransmitter increased within a short time after taking antidepressants, but the depressive symptoms were alleviated at least 2 weeks later, which suggests that the direct pathogenic factor of PSD is probably not the lack of monoamine neurotransmitters, but only an indirect factor 6 . Beyond that, theories of neuroanatomy (frontal-cortical circuit, cerebellar-hypothalamic pathway and amygdala anterior cingulate-cortical circuit damage) 7 , Glu/GABA neurotransmitter imbalance 8 , genetics 9 , neurotrophic hypothesis 10 can also partially explain the pathology and offer some aggressive treatment strategies. Nevertheless, current medical understanding of PSD is far from enough.…”