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[摘要]：To further improve the maximal serotonergic efficacy and better understand the configurational requirements for 5-HT1A binding and activation, we generated and biologically investigated structural variants of the lead structure befiradol. For a bioisosteric replacement of the 3-chloro-4-fluoro moiety. a focused library of 63 compounds by solution phase parallel synthesis was developed. Target binding of our compound collection was investigated, and their affinities for 5-HT2, alpha(1), and alpha(2)-adrenergic as well as D-1-D-4 at dopamine receptors were compared. For particularly interesting test compounds, intrinsic activities at 5-HT1A were examined in vitro employing a GTP gamma S assay. The investigation guided as to highly selective 5HT(1A) superagonists. The benzothiophene-3-carboxamide 8bt revealed almost exclusive 5HT(1A) recognition with a K-i value of 2.7 nM and a maximal efficacy of 124%. To get insights into the bioactive conformation of our compound collection, we synthesized conformation:Ally constrained bicyclic scaffolds when SAR data indicated a chair-type geometry and an equatorially dispositioned aminomethyl substituent for the 4,4-disubstituted piperidine moiety. |
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