Synthesis and biochemical evaluation of baclofen analogues locked in the baclofen solid-state conformation

J Med Chem. 1991 Apr;34(4):1307-13. doi: 10.1021/jm00108a011.


The synthesis of six close analogues of baclofen [3-(4-chlorophenyl)-4-aminobutyric acid] (BAC), a potent GABAB agonist, are reported. The compounds were designed starting from the structural informations contained in the solid state of BAC, regarded as a possible bioactive conformation, in which the p-chlorophenyl ring is perpendicular to the GABA backbone. A similar conformational situation was created by rigidifying the BAC structure by means of methylene (1), ethylene (2 and 6), or propylene (3) units, or by introducing chlorine atoms (4 and 5) into the ortho positions ("ortho effect"). Only compound 5 showed affinity for the GABAB receptor. Compound 6 [1-(aminomethyl)-5-chloro-2,3-dihydro-1H-indene-1-acetic acid], which was initially considered as representing the optimal mimic of the solid-state conformation of BAC, was surprisingly found inactive. An extensive conformational analysis was performed on compounds 1-6 in order to evaluate their flexibility and the overlap of their conformational population with respect to BAC. For this purpose a distance map was generated from three possible pharmacophoric groups: the amino and the carboxylic functions, and the phenyl ring. Finally, several explanations are proposed to account for the poor affinities of the prepared compounds such as steric hindrance or flexibility demand of the receptor.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Baclofen / analogs & derivatives*
  • Baclofen / chemical synthesis*
  • Baclofen / chemistry
  • Baclofen / pharmacology
  • Binding, Competitive
  • Cell Membrane / metabolism
  • Indicators and Reagents
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / metabolism*
  • Structure-Activity Relationship
  • X-Ray Diffraction
  • gamma-Aminobutyric Acid / chemistry
  • gamma-Aminobutyric Acid / metabolism


  • Indicators and Reagents
  • Receptors, GABA-A
  • gamma-Aminobutyric Acid
  • Baclofen