In this research work, we examined the decomposition mechanisms of -substituted diacetamides. We focused on the substituent effect on the nitrogen lone-pair electron delocalization, with electron-withdrawing and electron donor groups. DFT functionals used the following: B1LYP, B3PW91, CAMB3LYP, LC-BLYP, and X3LYP.
View Article and Find Full Text PDFWhile exploring the structure-activity relationship of 4-phenyl-2-dimethylaminotetralins (PATs) at serotonin 5-HT receptors, we discovered that relatively minor modification of PAT chemistry impacts function at 5-HT receptors. In HEK293 cells expressing human 5-HT receptors, for example, (-)-trans-3'-Br-PAT and (-)-trans-3'-Cl-PAT are agonists regarding Gα-inositol phosphate signaling, whereas (-)-trans-3'-CF-PAT is an inverse agonist. To investigate the ligand-receptor interactions that govern this change in function, we performed site-directed mutagenesis of 14 amino acids of the 5-HT receptor based on molecular modeling and reported G protein-coupled receptor crystal structures, followed by molecular pharmacology studies.
View Article and Find Full Text PDFThe human histamine H G-protein coupled receptor (GPCR) is an important drug target for inflammatory, sleep, and other neuropsychiatric disorders. To delineate molecular determinants for ligand binding for drug discovery purposes, human H receptor models were built by homology to the crystal structure of the human β adrenoceptor (βAR) and from the recently reported crystal structure of the human H receptor complex with doxepin at 3.1 Å (PDB code 3RZE).
View Article and Find Full Text PDFSpecific activation of serotonin (5-HT) 5-HT(2C) G protein-coupled receptors may be therapeutic for obesity and neuropsychiatric disorders. Mutagenesis coupled with computational and molecular modeling experiments based on the human β₂ adrenergic receptor structure was employed to delineate the interactions of different ligands at human 5-HT(2C) residues D3.32, S3.
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