RESUMO
A series of spiropiperidines was designed and synthesized by structural modifications based on our previous lead compound 1 and evaluated with cellular signaling assays for the discovery of 5-HT2C receptor (5-HT2CR) selective agonists with a Gq bias. Structure-activity relationship (SAR) studies of spiropiperidines uncovered spiro[chromene-2,4'-piperidine]s as a novel chemotype of 5-HT2CR selective agonists. Among this new series, the 7-chloro analogue 8 was identified as the most potent and selective 5-HT2CR partial agonist (Emax = 71.09%) with an EC50 value of 121.5 nM and no observed activity toward 5-HT2AR or 5-HT2BR. Moreover, compound 8 exhibited no recruitment activity for ß-arrestin and showed low inhibition of hERG at 10 µM. These findings may pave the way to develop more potent Gq-biased 5-HT2CR partial agonists as useful pharmacological tool compounds or potential drug candidates.
RESUMO
Aporphine alkaloids embedded in 4H-dibenzo[de,g]quinoline four-ring structures belong to one of the largest subclasses of isoquinoline alkaloids. Aporphine is a privileged scaffold in the field of organic synthesis and medicinal chemistry for the discovery of new therapeutic agents for central nervous system (CNS) diseases, cancer, metabolic syndrome, and other diseases. In the past few decades, aporphine has attracted continuing interest to be widely used to develop selective or multitarget directed ligands (MTDLs) targeting the CNS (e.g., dopamine D1/2/5, serotonin 5-HT1A/2A/2C and 5-HT7, adrenergic α/ß receptors, and cholinesterase enzymes), thereby serving as valuable pharmacological probes for mechanism studies or as potential leads for CNS drug discovery. The aims of the present review are to highlight the diverse CNS activities of aporphines, discuss their SAR, and briefly summarize general synthetic routes, which will pave the way for the design and development of new aporphine derivatives as promising CNS active drugs in the future.