Determination of rat brain and plasma levels of the orally active GABAB antagonist 3-amino-propyl-n-butyl-phosphinic acid (CGP 36742) by a new GC/MS method.
An involvement of GABAergic neurons has been suggested in the process of memory consolidation based on anatomical evidence and increasing physiological and biochemical data. With the advent of orally active GABAB antagonists, such as CGP 36742, the question of their therapeutic value, for example in Alzheimer's disease, becomes relevant. Therefore, a new GC/MS method was developed to determine the concentration of CGP 36742 (3-amino-propyl-n-butyl phosphinic acid) in various intra- and extracerebral tissues after different routes of application. The compound was chemically derivatised in a two-step process (acylation of the amino group and esterification of the phosphinic acid). The limit of detection of the method was 0.01 microgram/g tissue and 0.0005 microgram/mL plasma. The time-course after i.p. treatment showed peak levels of CGP 36742 between 30 min and 1 hr after injection. After a dose of 100 mg/kg, the concentration in the brain ranged from 1 to 1.4 microgram/g or 6 to 8 microM, assuming that 1 mg tissue equals 1 microL (i.e., below the IC50 of the interaction with GABAB receptors as measured by [3-3H]-aminopropyl-phosphinic acid binding [35 microM]). These results are discussed in light of the psychopharmacological effects (improvement of cognitive performance of rats) of CGP 36742 observed at very low oral doses.
Steulet
A F
AF
CNS Research, Pharmaceuticals Division, Ciby-Geigy Ltd., Basel, Switzerland.
Mobius
H J
HJ
Mickel
S J
SJ
Stocklin
K
K
Waldmeier
P C
PC
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism*; D018756:GABA Antagonists / Q000032:analysis*; D058787:GABA-A Receptor Antagonists; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D009943:Organophosphorus Compounds / Q000032:analysis* / Q000493:pharmacokinetics; D051381:Rats
D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D009943:Organophosphorus Compounds; C079148:(3-aminopropyl)(n-butyl)phosphinic acid