Synthesis of 3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles, displaying combined 5-HT uptake inhibiting and alpha(2)-adrenoceptor antagonistic activities: a novel series of potential antidepressants

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 16; pp. 2719 - 2725
• Main Authors: Andrés, J Ignacio, Alcázar, Jesús, Alonso, José M, Alvarez, Rosa M, Cid, José M, De Lucas, Ana I, Fernández, Javier, Martínez, Sonia, Nieto, Carmen, Pastor, Joaquín, Bakker, Margot H, Biesmans, Ilse, Heylen, Lieve I, Megens, Anton A
• Format: Journal Article
• Language: English
• Published: England 18.08.2003
• Subjects: Adrenergic alpha-Antagonists - chemical synthesis; Adrenergic alpha-Antagonists - pharmacology; Animals; Antidepressive Agents - chemical synthesis; Antidepressive Agents - pharmacology; Carrier Proteins - metabolism; Isoxazoles - chemical synthesis; Isoxazoles - pharmacology; Membrane Glycoproteins - metabolism; Membrane Transport Proteins; Molecular Structure; Nerve Tissue Proteins; Rats; Serotonin Plasma Membrane Transport Proteins; Serotonin Uptake Inhibitors - chemical synthesis; Serotonin Uptake Inhibitors - pharmacology; Stereoisomerism; Structure-Activity Relationship; Xylazine - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00525-0

The synthesis of a series of novel 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles as novel dual 5-HT reuptake inhibitors and alpha(2)-adrenoceptor antagonists is described. Their affinity at the three different human alpha(2)-adrenoceptor subtypes and the 5-HT transporter site is reported. The in vivo activity of the compounds was measured in two different assays: (1). inhibition of pCA-induced excitation, which evaluates the ability to block the central 5-HT transporter, and (2). inhibition of xylazine-induced loss of righting, which evaluates the ability to block central alpha(2)-adrenoceptors.