Novel Pyridylmethylamines as Highly Selective 5-HT1A Superagonists

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, α1, and α2-adrenergic as well as D1−D4 dopamine receptors were compared. For particularly interesting test compounds, intrinsic activities at 5-HT1A were examined in vitro employing a GTPγS assay. The investigation guided us to highly selective 5HT1A superagonists. The benzothiophene-3-carboxamide 8bt revealed almost exclusive 5HT1A recognition with a Ki 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 scaff...