نبذة مختصرة : BACKGROUND AND PURPOSE The 5-HT receptor (5-HTR) subtypes 5-HT2A and 5-HT2C are important neurotherapeutic targets, though, obtaining selectivity over 5-HT2B and closely related histamine H1 Rs is challenging. Here, we delineated molecular determinants of selective binding to 5-HT2A and 5-HT2C Rs for novel 4-phenyl-2-dimethylaminotetralins (4-PATs). EXPERIMENTAL APPROACH We synthesized 42 novel 4-PATs with halogen or aryl moieties at the C(4)-phenyl meta position. Affinity, function, molecular modeling, and 5-HT2A R mutagenesis studies were undertaken to understand structure-activity relationships at 5-HT2 -type and H1 Rs. Lead 4-PAT-type selective 5-HT2A /5-HT2C R inverse agonists were compared to pimavanserin, a selective 5-HT2A /5-HT2C R inverse agonist approved to treat psychoses, in the mouse head twitch response, and locomotor activity assays, as models relevant to antipsychotic drug development. KEY RESULTS Most 4-PAT diastereomers in the (2S,4R)-configuration bound non-selectively to 5-HT2A , 5-HT2C, and H1 Rs, with >100-fold selectivity over 5-HT2B Rs, whereas, diastereomers in the (2R,4R)-configuration bound preferentially to 5-HT2A over 5-HT2C Rs and had >100-fold selectivity over 5-HT2B and H1 Rs. Results suggest that G2385.42 and V2355.39 in 5-HT2A Rs (conserved in 5-HT2C Rs) are important for high affinity binding, whereas, interactions with T1945.42 and W1584.56 determine H1 R affinity. The 4-PAT (2S,4R)-2k, a potent and selective 5-HT2A /5-HT2C R inverse agonist, had activity like pimavanserin in the mouse head-twitch response assay, but was distinct in not suppressing locomotor activity. CONCLUSIONS AND IMPLICATIONS We provide evidence that the novel 4-PAT chemotype can yield selective 5-HT2A /5-HT2C R inverse agonists for antipsychotic drug development by optimizing ligand-receptor interactions in transmembrane domain 5. We also show that chirality can be exploited to attain selectivity over H1 Rs which may circumvent sedative effects.
Processing Request
No Comments.