Discovery of a New Series of Centrally Active Tricyclic Isoxazoles Combining Serotonin (5-HT) Reuptake Inhibition with α2-Adrenoceptor Blocking Activity
| Autor: | Margot H. Bakker, Ilse Biesmans, Anton Megens, Koen A. Hens, Sonia Martı́nez, J. Alonso, Joaquín Pastor, J.Ignacio Andrés, Ana Isabel de Lucas, Ilse Lenaerts, Javier Fernández, Thomas Steckler, Laura Iturrino, Luis M. Font, Patrick C. M. Vermote, José María Cid, Jesús Alcázar, Rosa M. Alvarez |
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| Rok vydání: | 2004 |
| Předmět: |
Tetrahydronaphthalenes
Stereochemistry Administration Oral Alpha (ethology) Pharmacology Structure-Activity Relationship In vivo Reflex Drug Discovery Adrenergic alpha-2 Receptor Agonists Animals Rats Wistar Serotonin Uptake Inhibitors chemistry.chemical_classification Chemistry Antagonist Stereoisomerism Isoxazoles Adrenergic alpha-2 Receptor Antagonists Medetomidine Antidepressive Agents Rats Quinolines Molecular Medicine Serotonin Enantiomer Reuptake inhibitor Heterocyclic Compounds 3-Ring Selective Serotonin Reuptake Inhibitors Tricyclic |
| Zdroj: | Journal of Medicinal Chemistry. 48:2054-2071 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm049619s |
| Popis: | 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 alpha(2)-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 alpha(2)-agonist medetomidine in rats confirmed the alpha(2)-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. |
| Databáze: | OpenAIRE |
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