Effects of sarizotan in animal models of ADHD: challenging pharmacokinetic-pharmacodynamic relationships.

摘要: Sarizotan 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-[[5-(4-fluorophenyl) pyridin-3-yl]methyl] methenamine, showed an in vivo pharmaco-EEG profile resembling that of methylphenidate which is used attention deficit/hyperactivity disorder (ADHD). In turn, we tested sarizotan against impulsivity juvenile rats measuring the choice for large delayed vs. a small immediate reward T-maze and obtained encouraging results starting at 0.03 mg/kg (plasma levels ~11 nM). Results from treated neonatally with 6-hydroxydopamine (6-OHDA), also supported anti-ADHD activity although 0.3 mg/kg. However, microdialysis studies revealed free brain concentration active doses were below its affinity 5-HT1A receptors, assumed primary target. contrast, electrophysiological experiments mid-brain Raphe serotonergic cells paralleled by plasma sampling there was ~60 % inhibition firing rate—indicating significant activation receptors—at 76 nM. line this, observed concentrations homogenates similar to total blood but over 500 fold higher than extracellular fluid (ECF) as measured using microdialysis. These data suggest may have potential effects low previously reported side-effects. Moreover, this case classical pharmacokinetic–pharmacodynamic relationship based on seems be less appropriate target engagement pharmacodynamic readouts.