Neurochemical profile in vitro of irindalone: A5‐HT2‐receptor antagonist

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Abstract
A new potential antihypertensive drug, irindalone (Lu 21‐098;(+)‐(1R,3S)‐1‐[2‐[4‐[3‐(p‐fluorophenyl)‐1‐indanyl]‐1‐piperazinyl] ‐ethyl]‐2‐imidazolidinone), has been characterized by a series of in vitro methods. Irindalone competitively inhibits peripheral and central serotonin2 (5‐HT2) receptors as measured by 5‐HT‐induced contractions of rabbit pulmonary artery and receptor binding methodology with 3H‐ketanserin as a ligand. The inhibitory effect on 5‐HT receptors is confirmed using other organs in vitro (rat stomach fundus, rat jugular vein, guinea pig trachea). Irindalone has lower affinity for α1‐adrenoceptors and histamine‐H1 receptors and only negligible affinity for α2‐adrenoceptors and muscarine cholinergic receptors. No inhibition of the uptake of noradrenaline (NA), dopamine (DA), or 5‐HT is seen. The neurochemical profile resembles that of ketanserin, which has slightly higher affinity for 5‐HT2 receptors. In the rat fundus, irindalone inhibits 5‐HT‐induced contractions, differing in this respect from ketanserin and cinanserin. Irindalone clearly deviates from the neuroleptics haloperidol and tefludazine, and from prazosin with which irindalone has been compared. The (‐)enantiomer of irindalone, Lu 21‐099, is considerably weaker than irindalone in the different test systems. Due to the strong blockade of 5‐HT2 receptors and the somewhat weaker blockade of α‐adrenoceptors, irindalone is expected to lower blood pressure potently and thus be a candidate for the treatment of hypertension.

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