Allosteric modulation by single enantiomers of a C3-chiral 1,4-benzodiazepine of the gamma aminobutyric acid type A receptor channel expressed in Xenopus oocytes.
Xenopus laevis oocytes injected with Poly(A)(+)-RNA isolated from neuronal tissue express membrane proteins peculiar to the origin of mRNA. The translation of gamma aminobutyric acid type A (GABAA) receptors has been shown by dose/ response behavior of GABA and the reversible blockade of the GABA-induced current by picrotoxin. This current was analyzed quantitatively under two electrode voltage-clamp conditions. This methodology has been applied for the first time to study the functional properties of the receptor as a function of the stereochemistry of the ligands. The (+)-S and (-)-R enantiomers of a water-soluble benzodiazepine derivative, 7-chloro-1,3-dihydro-3-hemisuccinyloxy-5-phenyl-1,4-benzodiazep in-2-one (OXHEM), obtained by preparative high performance liquid chromatographic (HPLC) resolution on chiral stationary phase, act as agonists in the in vitro modulation of the chloride channel. The (+)-S-OXHEM enantiomer was the more active.
Demuro
A
A
Dipartimento di Fisiologia e Biochimica G. Moruzzi, Pisa, Italy.
Burgio
M
M
Berton
F
F
Francesconi
W
W
Bertucci
C
C
D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D018118:Chloride Channels / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D004558:Electric Stimulation; D004594:Electrophysiology; D018755:GABA Agonists / Q000737:chemistry / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000502:physiology; D009865:Oocytes / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000096:biosynthesis / Q000737:chemistry; D051381:Rats; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D014982:Xenopus laevis
C106673:7-chloro-1,3-dihydro-3-hemisuccinyloxy-5-phenyl-1,4-benzodiazepin-2-one; D018118:Chloride Channels; D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D001569:Benzodiazepines