The action of new potent GABAB receptor antagonists in the hemisected spinal cord preparation of the rat.
CGP 52432 (3-N-(3,4-dichlorobenzyl)aminopropyl-P-diethoxymethylphosphinic acid), CGP 54062 (3-N[1-(R,S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-P-benzy l- phosphinic acid), CGP 54626 (3-N[[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)- hydroxypropyl-P-cyclohexylmethylphosphinic acid) and CGP 55845 (3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)- hydroxypropyl-P-benzyl-phosphinic acid) are novel selective GABAB receptor antagonist. The apparent Kd values for the complex formed between the GABAB receptor and these compounds were determined using the monosynaptic reflex in the hemisected rat spinal cord preparation in vitro. CGP 55845 was found to be the most potent GABAB receptor antagonist tested (apparent Kd = 30 nM). On the same preparation 0.3 microM CGP 55845 was equipotent with 100 microM of CGP 35348 (P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid) for reversal of the depressant action of (R)-(-)-baclofen.
Research and Development Department, Ciba-Geigy Ltd., Basel, Switzerland.
F
F
Brugger
U
U
Wicki
H R
HR
Olpe
W
W
Froestl
S
S
Mickel
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D058787:GABA-A Receptor Antagonists; D009943:Organophosphorus Compounds; D011963:Receptors, GABA-A; D001418:Baclofen