The kinetics, brain uptake and distribution of CL 275,838, a potential memory enhancer, and its main metabolites (II and IV) were evaluated in rats after intraperitoneal doses of 5, 10 and 20 mg/kg. Brain maximum concentrations (Cmax) of the three compounds after pharmacologically active doses were then related to the in vitro concentrations affecting some monoaminergic and amino acid receptor sites to examine the relative importance of these neurotransmitter systems in the pharmacological actions of CL 275,838. After 10 mg/kg CL 275,838, the unchanged compound rapidly entered the brain and distributed almost uniformly in various regions inside the blood-brain barrier. Its disappearance from brain and plasma was almost parallel with a comparable elimination half-life (t1/2) of about 2 h. Metabolite II entered the brain and equilibrated with plasma more slowly than the parent compound, achieving mean Cmax (0.2 μM) within 3 h of dosing. Metabolite IV was rapidly detected in rat brain but hardly amounted to 10% (0.1 μM) of the parent compound Cmax (1 μM). There was a linear relationship between dose and plasma and brain concentrations of the three compounds up to 20 mg/kg CL 275,838. At micromolar concentrations the parent compound had affinity for serotonin (5-HT) uptake sites, 5-HT2 and dopamine (DA2) receptors. Only at much higher concentrations than those achieved in vivo after pharmacologically active doses did it increase the binding of3H-glutamate to NMDA (N-methyl-d-aspartate) receptors. Metabolite II had a similar neurochemical profile. Metabolite IV had no affinity for these neurotransmitter systems, except for benzodiazepine (BDZ) receptor sites where it interacts with micromolar affinity behaving, however, as an agonist as determined by the GABA ratio. Although the 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 attenuate the impairment of a passive avoidance task caused by drugs or aging in rats.
- Brain uptake and distribution
- CL 275,838
- Neurotransmitter receptor affinities
ASJC Scopus subject areas