Monoacylglycerol lipase (MAGL) is a major serine hydrolase that hydrolyzes 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) and glycerol in the brain. Because 2-AG and AA are endogenous biologically active ligands in the brain, inhibition of MAGL is an attractive therapeutic target for CNS disorders, particularly neurodegenerative diseases. In this study, we report the structure-based drug design of novel piperazinyl pyrrolidin-2-ones starting from our hit compounds 2a and 2b. By enhancing the interaction of the piperazinyl pyrrolidin-2-one core and its substituents with the MAGL enzyme via design modifications, we identified a potent and reversible MAGL inhibitor, compound (R)-3t. Oral administration of compound (R)-3t to mice decreased AA levels and elevated 2-AG levels in the brain.
[structure: see text] A receptor 1 with phenolphthalein and two crown ethers in the molecule develops brilliant purple color in the presence of dipeptides with a specific amino acid-sequence containing a C-terminal lysine. This type of color development could be extended to the detection of oligopeptides of a specific sequence at the N-terminal such as scyliorhinin I and APP(770)(394-410).
[structure: see text] Optically active artificial host molecules 2-5 based on a phenolphthalein skeleton have been prepared for visual enantiomeric recognition of alanine derivatives 8 and 9. The receptor 3 discriminates (R)-8 and (R)-9 from (S)-8 and (S)-9, respectively, to develop a purple color.
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