Discovery of a New Series of Centrally Active Tricyclic Isoxazoles Combining Serotonin (5-HT) Reuptake Inhibition with α2-Adrenoceptor Blocking Activity

• Published in: Journal of medicinal chemistry 2005-03, Vol.48 (6), p.2054-2071
• Main Authors: Andrés, J. Ignacio, Alcázar, Jesús, Alonso, José M, Alvarez, Rosa M, Bakker, Margot H, Biesmans, Ilse, Cid, José M, De Lucas, Ana I, Fernández, Javier, Font, Luis M, Hens, Koen A, Iturrino, Laura, Lenaerts, Ilse, Martínez, Sonia, Megens, Anton A, Pastor, Joaquín, Vermote, Patrick C. M, Steckler, Thomas
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049619s

The synthesis and pharmacology of a new series of 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles that combine central serotonin (5-HT) reuptake inhibition with α2-adrenoceptor blocking activity is described as potential antidepressants. Four compounds were selected for further evaluation, and the combination of both activities was found to be stereoselective, residing mainly in one enantiomer. Reversal of the loss of righting induced by the α2-agonist medetomidine in rats confirmed the α2-adrenoceptor blocking activity in vivo and also demonstrated CNS penetration. Antagonism of p-chloroamphetamine (pCA)-induced excitation as well as blockade of the neuronal 5-HT depletion induced by p-CA administration in rats confirmed their ability to block the central 5-HTT, even after oral administration. Replacement of the oxygen atom at the 5-position of the tricyclic scaffold by a nitrogen or a carbon atom, as well as O-substitution at position 7, led also to active compounds, both in vitro and in vivo.