The extracellular entrance provides selectivity to serotonin 5-HT7 receptor antagonists with antidepressant-like behavior in vivo

  • J Med Chem. 2014 Aug 14;57(15):6879-84. doi: 10.1021/jm500880c.
Rocío A Medina  1 ,  Henar Vázquez-Villa ,  José C Gómez-Tamayo ,  Bellinda Benhamú ,  Mar Martín-Fontecha ,  Tania de la Fuente ,  Gianluigi Caltabiano ,  Peter B Hedlund ,  Leonardo Pardo ,  María L López-Rodríguez
Affiliations
  • 1. Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid , E-28040 Madrid, Spain.
PMID: 25073094 DOI: 10.1021/jm500880c
Abstract

The finding that ergotamine binds serotonin receptors in a less conserved extended binding pocket close to the extracellular entrance, in addition to the orthosteric site, allowed us to obtain 5-HT7R antagonist 6 endowed with high affinity (Ki=0.7 nM) and significant 5-HT1AR selectivity (ratio>1428). Compound 6 exhibits in vivo antidepressant-like effect (1 mg/kg, IP) mediated by the 5-HT7R, which reveals its interest as a putative research tool or pharmaceutical in depression disorders.