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.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter, plays a critical role in the regulation of various neurological functions, including mood, sleep, cognition, anxiety, sexual behavior, and appetite [1,2]
Based on the molecular docking study of several 5-HT2C agonists published in literature [27,28], we assumed that the terminal-free amine of the piperazine moiety could be a key functional group binding to a conserved residue, D134, in 5-HT2C protein
8 derived from (R)-isomer of secondary benzyl alcohol showed better binding affinity and selectivity to 5-HT2C than its diastereomer [22], we designed an alternative series of pyrimidine derivatives 10 possessing a variety of cyclic amines to examine their agonistic effect on 5-HT receptor activation
Summary
Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter, plays a critical role in the regulation of various neurological functions, including mood, sleep, cognition, anxiety, sexual behavior, and appetite [1,2]. Activation of the 5-HT receptors induces both inhibitory and excitatory signal transduction by modulating the release of many neurotransmitters, such as glutamate, dopamine, epinephrine, and acetylcholine. They have been considered crucial therapeutic targets for a variety of neurological diseases, including depression, psychiatric disorders, sexual dysfunction, obesity, and urinary incontinence [3,4,5]. The 5-HT2 receptors comprise three subtypes: 5-HT2A , 5-HT2B , and 5-HT2C. One of the crucial problems faced during the development of 5-HT2C agonists is selectivity over the structurally related 5-HT2A and 5-HT2B receptors. One of the crucial problems faced during the development of 5-HT2C agonists is selectivity over the structurally related 5-HT2A and 5-HT2B receptors. 5-HT2A agonism in humans is implicated in acute adverse effects, such as Molecules 2019, 24, 3234; doi:10.3390/molecules24183234 www.mdpi.com/journal/molecules
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