Synthesis and biological evaluation of GABA derivatives able to cross the blood-brain barrier in rats

Bioorg Med Chem Lett. 2003 Nov 3;13(21):3765-9. doi: 10.1016/j.bmcl.2003.07.004.

Abstract

Two new GABA derivatives, 1 and 2, were synthesized and tested for their capacity to display CNS activity, which was assessed by determining the effects on the duration of pentobarbital-induced hypnosis in rats. Compound 1, peripherally injected, significantly prolonged the hypnosis time, a typical GABA-mimetic effect, while both intracerebroventricular and intravenous administration of compound 2 surprisingly shortened the hypnotic effect in an atropine-sensitive way. The study was extended also to compounds 1a, 1b and 2a, putative oxidative/hydrolytic metabolites of 1 and 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atropine / pharmacology
  • Binding, Competitive
  • Biotransformation
  • Blood-Brain Barrier / drug effects*
  • Dose-Response Relationship, Drug
  • Female
  • Hydrolysis
  • Hypnotics and Sedatives / pharmacology
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Injections, Intraventricular
  • Magnetic Resonance Spectroscopy
  • Muscarinic Antagonists / pharmacology
  • Oxidation-Reduction
  • Pentobarbital / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / metabolism
  • Receptors, GABA-B / drug effects
  • Receptors, GABA-B / metabolism
  • Sleep / drug effects
  • gamma-Aminobutyric Acid / analogs & derivatives*
  • gamma-Aminobutyric Acid / metabolism
  • gamma-Aminobutyric Acid / pharmacokinetics*

Substances

  • Hypnotics and Sedatives
  • Muscarinic Antagonists
  • Receptors, GABA-A
  • Receptors, GABA-B
  • gamma-Aminobutyric Acid
  • Atropine
  • Pentobarbital