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In vivo pharmacology of irindalone, a 5‐HT 2 receptor antagonist with predominant peripheral effects
Author(s) -
Arnt Jørn,
Bøgesø Klaus P.,
Boeck Vita,
Christensen Anne V.,
Dragsted Nils,
Hyttel John,
Skarsfeldt Torben
Publication year - 1989
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430160107
Subject(s) - ketanserin , quipazine , agonist , pharmacology , chemistry , antagonist , phenylephrine , in vivo , antagonism , spiperone , receptor antagonist , receptor , 5 ht receptor , serotonin , endocrinology , medicine , biology , biochemistry , microbiology and biotechnology , blood pressure
The in vivo effects of irindalone, a newly developed serotonin 2 (5‐HT 2 ) 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 α 1 ‐adrenoceptor agonist phenylephrine. Irindalone is relatively weak in rat models detecting central 5‐HT 2 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 3 H‐ketanserin binding in frontal cortex. Irindalone weakly antagonizes the flexor reflex stimulated by the α 1 ‐adrenoceptor agonist St 587. No dopamine receptor inhibition is detected in the methylphenidate gnawing test in mice. High bioavailability is indicated by the identical ED 50 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‐HT 2 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‐HT 2 receptor antagonism develops using this dose regimen. It is concluded that irindalone is a potent 5‐HT 2 antagonist with preferential effects at peripheral sites.