The preclinical pharmacologic profile of tiapride.

Tiapride is a benzamide derivative that has been used successfully in the clinic for a number of years for the treatment of agitation and aggressiveness in elderly patients. Like many substituted benzamides, tiapride specifically blocks dopamine receptors in the brain. It has affinity for dopamine D(2) (IC(50) = 110-320 nM) and D(3) (IC(50) = 180 nM) receptors in vitro but lacks affinity for dopamine D(1) and D(4) receptors and for non-dopaminergic receptors including H(1), alpha(1), alpha(2)-adrenergic and serotonergic receptors. Tiapride also shows dose-related inhibition of [3H]-raclopride binding in limbic areas and in the striatum of the rat in vivo (ED(50) approximately 20 mg/kg, ip). In microdialysis experiments, tiapride (over the range 10-30 mg/kg, ip) increased extracellular levels of dopamine in the nucleus accumbens and striatum, a reflection of its blockade of postsynaptic dopamine receptors in these brain areas. In behavioral experiments in rats, lower doses of tiapride (ED(50) = 10 mg/kg, ip) antagonised dopamine agonist-induced hyperactivity while higher doses (ED(50) = 60 mg/kg, ip) were required to block stereotyped movements. In addition, doses of tiapride up to 200 mg/kg, ip failed to induce catalepsy, an effect observed with many other drugs which block dopamine receptors. In tests of conditioned behavior in rats, tiapride was found to give rise to an interoceptive stimulus associated with dopamine receptor blockade at doses (ED(50) = 2.2 mg/kg, ip) much lower than those producing motor disturbances or sedation (ED(50) = 40 mg/kg, ip), in striking contrast to a range of conventional or atypical neuroleptics that produced interoceptive stimulus and sedation at similar doses. Furthermore, the acquisition by rats of a place-learning task in a water maze was not affected by tiapride (over the range 3-30 mg/kg, ip), whereas haloperidol (MED = 0.25 mg/kg, ip) and risperidone (MED = 0.03 mg/kg, ip) impaired performance. The preclinical pharmacologic and behavioral profile of tiapride suggests that its clinical activity may be due to a selective blockade of dopamine D(2) and D(3) receptors in limbic brain regions. The results are also consistent with a lack of motor or cognitive side effects.