Preclinical pharmacology of flesinoxan: A potential anxiolytic and antidepressant drug

Receptor binding studies revealed that flesinoxan potently and selectively binds to the 5-HT1A receptor (Ki = 1.7 nM). The anatomical distribution of [3H]-flesinoxan binding sites is very similar to the localization of the 5-HT1A sites labelled by [3H]-8-OH-DPAT. In several functional models flesinoxan acted as a 5-HT1A agonist. Flesinoxan has been investigated in a variety of animal models predictive for anxiolytic activity. In a conflict test in pigeons, flesinoxan has potent anxiolytic activity at low doses (0.03–1 mg/kg i.m.). Flesinoxan is also highly active to reduce separation-induced ultrasonic anxiety calls in infant rats and in an anticipatory anxiety model in adult mice. However, in the four-plate test and the light-dark model in mice, flesinoxan and other 5-HT1A agonists had no anxiolytic effects. Antidepressant properties of flesinoxan were shown in a behavioural despair model in rats: the forced-swim test. Flesinoxan was more active (0.2–1.8 mg/kg s.c.) than classical tricyclic antidepressants. The putative antidepressant properties are also supported by the desensitisation of β-adrenergic receptors in rats after subchronic administration of flesinoxan. In a functional test for β-receptor activity in the brain (noradrenaline induced c-AMP production in brain slices), a reduction of responsivity was observed after 2 weeks of treatment with flesinoxan (6 mg/kg/day). Therefore, based on the animal pharmacology there are strong indications that flesinoxan as a selective 5-HT1A agonist, has anxiolytic as well as antidepressant properties in man.