Novel pyridylmethylamines as highly selective 5-HT_(1A) superagonists

摘要

To further improve the maximal serotonergic efficacy and better understand the configurational requirements for 5-HT_(1A) 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-HT_2, α_1, and α_2-adrenergic as well as D_1-D_4 dopamine receptors were compared. For particularly interesting test compounds, intrinsic activities at 5-HT_(1A) were examined in vitro employing a GTPγS assay. The investigation guided us 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 conformationally constrained bicyclic scaffolds when SAR data indicated a chair-type geometry and an equatorially dispositioned aminomethyl substituent for the 4,4-disubstituted piperidine moiety.