U-89843A is a novel allosteric modulator of gamma-aminobutyric acidA receptors.
A group of pyrrolopyrimidine derivatives were examined for their interaction with rat recombinant gamma-aminobutyric acid (GABA)A receptors using the whole cell patch clamp and equilibrium binding techniques. In the alpha 1 beta 2 gamma 2 subtype of GABAA receptors expressed in human embryonic kidney cells, a prototype pyrrolopyrimidine, U-89843A (7H-pyrrol[2,3-d]pyrimidine,6,7-methyl-2,4-di- 1-pyrrolidinyl,hydrochloride), dose-dependently enhanced 5 microM GABA-induced Cl- currents with a maximal enhancement of 362 +/- 91%, a half-maximal concentration of 2 +/- 0.4 microM and a slope factor of 1.1 +/- 0.4. The drug also inhibited [35S]t-butylbicyclophosphorothionate binding in rat cerebrocortical membranes with a similar half-maximal inhibitory concentration. The enhancement of Cl- currents by U-89843A was insensitive to Ro 15-1788 (a benzodiazepine antagonist), was also observed in the alpha 3 beta 2 gamma 2 and alpha 6 beta 2 gamma 2 subtypes (no selectivity to different alpha-isoforms unlike many benzodiazepines), but was absent in the receptor subtypes consisting of two subunits (alpha 1 beta 2, alpha 1 gamma 2 and beta 2 gamma 2). It has been known that neurosteroids and barbiturates are uniformly active in both the two subunit receptors, substituted pyrazinones are only active in the alpha 1 beta 2 subtype and loreclezole is active in the subtypes containing beta 2. We propose that U-89843A interacts with an allosteric site on GABAA receptors distinct from the sites for benzodiazepines, barbiturates, neurosteroids, substituted pyrazinones or loreclezole.(ABSTRACT TRUNCATED AT 250 WORDS)
Im
H K
HK
Central Nervous System Diseases Research, Upjohn Company, Kalamazoo, Michigan, USA.
Im
W B
WB
Pregenzer
J F
JF
Carter
D B
DB
Hamilton
B J
BJ
D000494:Allosteric Regulation; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002460:Cell Line; D065101:Chloride Channel Agonists; D002712:Chlorides / Q000378:metabolism; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D065101:Chloride Channel Agonists; D002712:Chlorides; D018757:GABA Modulators; D011743:Pyrimidines; D011758:Pyrroles; D011963:Receptors, GABA-A; C097295:U 89843; C037476:tert-butylbicyclophosphorothionate