Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT2C Agonists

Abstract

Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT2C agonists. To improve selectivity for 5-HT2C over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-position or 4-position and varying cyclic amines at the 2-position. The in vitro cell-based assay and binding assay identified compounds 10a and 10f as potent 5-HT2C agonists. Further studies on selectivity to 5-HT subtypes and drug-like properties indicated that 2,4-disubstituted pyrimidine 10a showed a highly agonistic effect on the 5-HT2C receptor, with excellent selectivity, as well as exceptional drug-like properties, including high plasma and microsomal stability, along with low CYP inhibition. Thus, pyrimidine 10a could be considered a viable lead compound as a 5-HT2C selective agonist.

Antidepressant-Like Effect of a Selenoindolizine in Mice: In Vivo and In Silico Evidence for the Involvement of the Serotonergic 5-HT2A/C Receptors

“…In this way, Sel showed a strong affinity with 5-HT 2A and 5-HT 2C receptors in the molecular docking studies. The interactions between Sel and 5-HT 2A/C amino acid residues are similar to those of other ligands of 5-HT 2A/C receptors. ,,,,, However, further studies are needed to elucidate if SeI binds 5-HT 2A and 5-HT 2C receptors and how these possible interactions affect the 5-HT 2A/C receptors.…”

“…In the 5-HT 2C receptor docking study, Sel made pi–alkyl hydrophobic interactions with Val215, Val135, Phe328, Phe223, Trp324, and hydrogen bonds with Ala222 (Figure B). The hydrophobic contact with Val135, Phe328, Trp324, and Val215 also has been described and could be relevant to the action of 5-HT 2C ligands. , The residues Val135 and Phe328 of the 5-HT 2C receptor have been related to the binding of 5-HT 2C antagonists. However, a comparison among 5-HT 2C agonists and antagonist binding modes demonstrated that they share the same pocket with a different orientation …”

Effect of Lactobacillus acidophilus Fermentation on the Quality of Glutinous Rice Products

“…[ 11 ] Lactic acid bacteria are often used as microbial starter for rice fermented products, and a variety of organic acids are produced during the fermentation process, resulting in acidification, which can also mask the unpleasant smell of the product itself. [ 12,13 ] Lactobacillus spp. is the dominant bacterial genus for fermenting sticky rice products.…”

Identification of Spiro[chromene-2,4′-piperidine]s as Potent, Selective, and Gq-Biased 5-HT2C Receptor Partial Agonists

“…To date, many efforts have been made to identify 5-HT 2C R agonists − and positive allosteric modulators. − 5-HT 2C R agonists generally possess a high structural similarity to the endogenous ligand serotonin (5-HT), as depicted in Figure and Figure S1, consisting of a basic amine, an aromatic ring, and a linker connecting them. Only lorcaserin has once been approved by the FDA as a selective 5-HT 2C R agonist for the treatment of obesity; unfortunately, it was later withdrawn from the market due to concerns regarding potential increased risk of cancer associated with long-term use .…”