BRAIN UPTAKE AND DISTRIBUTION OF THE POTENTIAL MEMORY ENHANCER CL-275,838 AND ITS MAIN METABOLITES IN RATS - RELATIONSHIP BETWEEN BRAIN CONCENTRATIONS AND IN-VITRO POTENCIES ON NEUROTRANSMITTER MECHANISMS

The kinetics, brain uptake and distribution of CL 275, 838, a potentia l memory enhancer, and its main metabolites (II and IV) were evaluated in rats after intraperitoneal doses of 5, 10 and 20 mg/kg. Brain maxi mum concentrations (C-max) of the three compounds after pharmacologica lly active doses were then related to the in vitro concentrations affe cting some monoaminergic and amino acid receptor sites to examine the relative importance of these neurotransmitter systems in the pharmacol ogical actions of CL 275,838. After 10 mg/kg CL 275, 838, the unchange d compound rapidly entered the brain and distributed almost uniformly in various regions inside the blood-brain barrier. Its disappearance f rom brain and plasma was almost parallel with a comparable elimination half-life (t(1/2)) of about 2 h. Metabolite II entered the brain and equilibrated with plasma more slowly than the parent compound, achievi ng mean C-max (0.2 mu M) within 3 h of dosing. Metabolite IV was rapid ly detected in rat brain but hardly amounted to 10% (0.1 mu M) Of the parent compound C-max (1 mu M). There was a linear relationship betwee n dose and plasma and brain concentrations of the three compounds up t o 20 mg/kg CL 275, 838. At micromolar concentrations the parent compou nd had affinity for serotonin (5-HT) uptake sites, 5-HT, and dopamine (DA(2)) receptors. Only at much higher concentrations than those achie ved in vivo after pharmacologically active doses did it increase the b inding of H-3-glutamate to NMDA (N-methyl-D-aspartate) receptors. Meta bolite II had a similar neurochemical profile. Metabolite IV had no af finity for these neurotransmitter systems, except for benzodiazepine ( BDZ) receptor sites where it interacts with micromolar affinity behavi ng, however, as an agonist as determined by the GABA ratio. Although t he effect on NMDA is compatible with favourable effects on memory, it is unlikely that it is involved in the ability of CL 275,838 to attenu ate the impairment of a passive avoidance task caused by drugs or agin g in rats.