DETERMINATION OF RAT-BRAIN AND PLASMA-LEVELS OF THE ORALLY-ACTIVE GABA(B) ANTAGONIST 3-AMINO-PROPYL-N-BUTYL-PHOSPHINIC ACID (CG-36742) BY ANEW GC MS METHOD/

An involvement of GABAergic neurons has been suggested in the process of memory consolidation based on anatomical evidence and increasing ph ysiological and biochemical data. With the advent of orally active GAB A(B) antagonists, such as CGP 36742, the question of their therapeutic value, for example in Alzheimer's disease, becomes relevant. Therefor e, a new GC/MS method was developed to determine the concentration of CGP 36742 (3-amino-propyl-n-butyl phosphinic acid) in various intra- a nd extracerebral tissues after different routes oi application. The co mpound 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 p lasma. 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 IC50 of the interaction with GABA(B) receptors as measured by [3-H-3]-amin opropyl-phosphinic acid binding [35 mu M]). These results are discusse d in light of the psychopharmacological effects (improvement of cognit ive performance of rats) of CGP 36742 observed at very low oral doses.