Determination of rat brain and plasma levels of the orally active GABA sub(B) antagonist 3-amino-propyl-n-butyl-phosphinic acid (CGP 36742) by a new GC/MS method

• Published in: Biochemical pharmacology 1996-03, Vol.51 (5), p.613-619
• Main Authors: Steulet, A-F, Moebius, H-J, Mickel, S J, Stoecklin, K, Waldmeier, P C
• Format: Article
• Language: English
• ISSN: 0006-2952

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 GABA sub(B) 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 mu g/g tissue and 0.0005 mu g/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 mu g/g or 6 to 8 mu M, assuming that 1 mg tissue equals 1 mu L (i.e., below the IC sub(50) of the interaction with GABA sub(B) receptors as measured by [3- super(3)H]-aminopropyl-phosphinic acid binding [35 mu M]). 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.