Synthesis and biological evaluation of GABA derivatives able to cross the blood-brain barrier in rats.
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.
Carelli
Vincenzo
V
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università La Sapienza, Piazzale A. Moro 5, 00185 Rome, Italy. vincenzo.carelli@uniroma1.it
Liberatore
Felice
F
Scipione
Luigi
L
Giorgioni
Gianfabio
G
Di Stefano
Antonio
A
Impicciatore
Mariannina
M
Ballabeni
Vigilio
V
Calcina
Francesco
F
Magnanini
Francesca
F
Barocelli
Elisabetta
E
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001667:Binding, Competitive; D001711:Biotransformation; D001812:Blood-Brain Barrier / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006868:Hydrolysis; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D009682:Magnetic Resonance Spectroscopy; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010084:Oxidation-Reduction; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism; D012890:Sleep / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*
D006993:Hypnotics and Sedatives; D018727:Muscarinic Antagonists; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D001285:Atropine; D010424:Pentobarbital