Comparative molecular field analysis of fenoterol derivatives: A platform towards highly selective and effective beta(2)-adrenergic receptor agonists

Bioorg Med Chem. 2010 Jan 15;18(2):728-36. doi: 10.1016/j.bmc.2009.11.062. Epub 2009 Dec 6.

Abstract

Purpose: To use a previously developed CoMFA model to design a series of new structures of high selectivity and efficacy towards the beta(2)-adrenergic receptor.

Results: Out of 21 computationally designed structures 6 compounds were synthesized and characterized for beta(2)-AR binding affinities, subtype selectivities and functional activities.

Conclusion: the best compound is (R,R)-4-methoxy-1-naphthylfelnoterol with K(i)beta(2)-AR=0.28microm, K(i)beta(1)-AR/K(i)beta(2)-AR=573, EC(50cAMP)=3.9nm, EC(50cardio)=16nm. The CoMFA model appears to be an effective predictor of the cardiomocyte contractility of the studied compounds which are targeted for use in congestive heart failure.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists*
  • Binding Sites
  • Cell Line
  • Fenoterol / chemical synthesis
  • Fenoterol / chemistry
  • Fenoterol / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Receptors, Adrenergic, beta-2 / immunology
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Adrenergic beta-2 Receptor Agonists
  • Receptors, Adrenergic, beta-2
  • Fenoterol