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

J Med Chem. 2010 Oct 14;53(19):7167-79. doi: 10.1021/jm100835q.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Animals
  • Azabicyclo Compounds / chemical synthesis*
  • Azabicyclo Compounds / chemistry
  • Azabicyclo Compounds / pharmacology
  • Binding Sites
  • Binding, Competitive
  • CHO Cells
  • Corpus Striatum / metabolism
  • Cricetinae
  • Cricetulus
  • Humans
  • In Vitro Techniques
  • Methylamines / chemical synthesis*
  • Methylamines / chemistry
  • Methylamines / pharmacology
  • Models, Molecular
  • Molecular Conformation
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Radioligand Assay
  • Serotonin 5-HT1 Receptor Agonists*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Swine
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology

Substances

  • Amides
  • Azabicyclo Compounds
  • Methylamines
  • Pyridines
  • Serotonin 5-HT1 Receptor Agonists
  • Thiophenes