Novel pyridylmethylamines as highly selective 5-HT(1A) superagonists.
Basic Information
ID: ALA1255227
Journal: J Med Chem
Title: Novel pyridylmethylamines as highly selective 5-HT(1A) superagonists.
Authors: Bollinger S, Hübner H, Heinemann FW, Meyer K, Gmeiner P.
Abstract: 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.
CiteXplore: 20860381
DOI: 10.1021/jm100835q
Patent ID: ┄