In vivo pharmacology of irindalone,a 5-HT2 receptor antagonist with predominant peripheral effects

The in vivo effects of irindalone, a newly developed serotonin₂ (5-HT₂) antagonist, have been investigated in comparison with a series of reference compounds. Irindalone potently antagonizes the pressor response induced by 5-HT in pithed rats, but has a 173 times weaker effect against the α₁-adrenoceptor agonist phenylephrine. Irindalone is relatively weak in rat models detecting central 5-HT₂ antagonism, that is, inhibition of quipazine- or I-5-HTP plus citalopram-induced head twitches, inhibition of I-5-HTP plus citalopram-induced increases of flexor reflexes, and inhibition of the discriminative stimulus properties induced by d-LSD. Furthermore, it displaces in vivo ³H-ketanserin binding in frontal cortex. Irindalone weakly antagonizes the flexor reflex stimulated by the α₁-adrenoceptor agonist St 587. No dopamine receptor inhibition is detected in the methylphenidate gnawing test in mice. High bioavailability is indicated by the identical ED₅₀ values obtained in the head twitch model after s.c. and p.o. administration. The activity profile of irindalone resembles that of ketanserin except in two characteristics: ketanserin has greater potency than irindalone as an antagonist in the 5-HTP-induced flexor reflex, but has a shorter duration of action. The effect of irindalone is stereoselective, since its opposite enantiomer Lu 21-099 is almost inactive in the models for central and peripheral 5-HT₂ receptor antagonism. Finally, the effect of repeated treatment with irindalone (18 μmol/kg, p.o., twice daily for 2 weeks) on inhibition of quipazine-induced head twitches was studied. Two days after the last dose, the potency for inhibiting quipazine was unchanged, indicating that no tolerance to 5-HT₂ receptor antagonism develops using this dose regimen. It is concluded that irindalone is a potent 5-HT₂ antagonist with preferential effects at peripheral sites.