A novel selective GABA(A) alpha1 receptor agonist displaying sedative and anxiolytic-like properties in rodents

J Med Chem. 2005 Oct 20;48(21):6756-60. doi: 10.1021/jm058002n.

Abstract

In our pursuit to identify selective ligands for Bz/GABA(A) receptor subtypes, a novel pyrazolo[1,5-a]pyrimidine derivative (4), the azaisostere of zolpidem, was synthesized and evaluated in vitro on bovine brain homogenate and on recombinant benzodiazepine receptors (alphaxbeta2/3gamma2, x = 1-3, 5) expressed in HEK293 cells. Compound 4 displayed affinity only for alpha1beta2gamma2 subtype (K(i) = 31 nM), and in an in-depth, in vivo study it revealed sedative and anxiolytic-like properties without any amnesic and myorelaxant effects in rodents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / chemical synthesis*
  • Anti-Anxiety Agents / chemistry
  • Anti-Anxiety Agents / pharmacology
  • Anticonvulsants / chemical synthesis
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacology
  • Avoidance Learning / drug effects
  • Binding, Competitive
  • Brain / metabolism
  • Cattle
  • Cell Line
  • GABA-A Receptor Agonists*
  • Humans
  • Hypnotics and Sedatives / chemical synthesis*
  • Hypnotics and Sedatives / chemistry
  • Hypnotics and Sedatives / pharmacology
  • In Vitro Techniques
  • Mice
  • Muscle Relaxation / drug effects
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / physiology
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, GABA-A
  • Recombinant Proteins / metabolism

Substances

  • Anti-Anxiety Agents
  • Anticonvulsants
  • GABA-A Receptor Agonists
  • GABRA1 protein, human
  • Gabra1 protein, mouse
  • Hypnotics and Sedatives
  • N,N-dimethyl-(2-(4-methylphenyl)-5-methylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide
  • Pyrazoles
  • Pyrimidines
  • Receptors, GABA-A
  • Recombinant Proteins