Arylalkylamines are a novel class of positive allosteric modulators at GABA(B) receptors in rat neocortex.
Using grease-gap recording from rat neocortical slices, the gamma-aminobutyric acid(B) (GABA(B)) receptor agonists baclofen (3-100 microM) and SKF 97541 (3-aminopropyl-methylphosphinic acid) (1-30 microM) elicited reversible and concentration-dependent hyperpolarizing responses, with EC(50) values of 10 and 3 microM, respectively. The hyperpolarizations were antagonised by the GABA(B) receptor antagonist Sch 50911 ((+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid) (1, 5 and 10 microM). Fendiline (N-[3,3-diphenylpropyl)-alpha-methylbenzylamine) (5-50 microM) and its congeners, prenylamine (N-[3,3-diphenylpropyl)-alpha-methylphenylethylamine) (10-100 microM) and F551 (N-[3,3-diphenylpropyl)-alpha-methyl-3-methoxybenzylamine) (1-30 microM) reversibly enhanced hyperpolarizing responses to the agonists; such effects were reduced by Sch 50911. These arylalkylamines produced leftward shifts of the concentration-response curves, with a marked increase in the maximal hyperpolarization obtained, compared with the agonists alone, F551 being the most potent. These findings suggest that these arylalkylamines represent a new class of positive modulators of GABA(B) receptor-mediated function.
Kerr
David I B
DI
Department of Anaesthesia and Intensive Care, The University of Adelaide, Adelaide, South Australia 5005, Australia.
Ong
Jennifer
J
Puspawati
Ni Made
NM
Prager
Rolf H
RH
D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D004357:Drug Synergism; D005275:Fendiline / Q000494:pharmacology*; D058786:GABA-B Receptor Agonists; D008297:Male; D019579:Neocortex / Q000187:drug effects*; D011299:Prenylamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D058786:GABA-B Receptor Agonists; D001418:Baclofen; D011299:Prenylamine; D005275:Fendiline