7-Chloro-3-methyl-3-4-dihydro-2H-1,2,4 benzothiadiazine S,S-dioxide (IDRA 21): a benzothiadiazine derivative that enhances cognition by attenuating DL-alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor desensitization.
7-Chloro-3-Methyl-3-4-Dihydro-2H-1,2,4 Benzothiadiazine S,S Dioxide (IDRA 21), which attenuates the rapid autodesensitization of DL-alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA)-selective glutamate receptors and increases excitatory synaptic strength, improves cognition (learning and memory), as revealed by its ability to improve performance in water maze and passive avoidance tests in rats. Normal rats trained to (15-20 sec) reach the exit platform rapidly in a water maze that included four incorrect choices were given oral IDRA 21 (4-120 mumol/kg) or vehicle and then exposed to a delayed retention trial in a maze that included seven incorrect choices. In this retention trial, the IDRA 21-treated rats performed considerably better than those that received the vehicle. Moreover, oral IDRA 21 (ED50 = 7.6 microM) attenuated the performance impairment induced by the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (F) quinoxaline in the water maze test. In this test and in a passive avoidance test, the performance impairment elicited by alprazolam, a full allosteric modulator at gamma-aminobutyric acid-A receptors, or by scopolamine, a competitive muscarinic receptor antagonist, was also reduced by oral administration of IDRA 21 (ED50 = 13 and 108 mumol/kg, against alprazolam and scopolamine, respectively); in all these tests, IDRA 21 was 20- to 30-fold more potent than aniracetam. Because IDRA 21 is a racemic molecule; the two stereoisomers were isolated and studied behaviorally. Only the (+) form was found to be behaviorally active. These results indicate that IDRA 21 given orally to rats presumably crosses the blood-brain barrier and acts stereoselectively on specific receptors that were operative during this behavioral procedure. Because the activity of IDRA 21 on rat cognition tests appears to be related to its ability to potentiate AMPA-activated currents, one can suggest that IDRA 21 improves cognition by acting on a stereoselective site of AMPA receptor that is operative in attenuating the rapid autodesensitization of these receptors.
Zivkovic
I
I
Center for Neuropharmacology, Nathan S. Kline Institute for Psychiatric Research, NYU, Orangeburg.
Thompson
D M
DM
Bertolino
M
M
Uzunov
D
D
DiBella
M
M
Costa
E
E
Guidotti
A
A
D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001581:Benzothiadiazines / Q000494:pharmacology*; D001921:Brain / Q000502:physiology*; D002740:Chlorothiazide / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D003981:Diazoxide / Q000494:pharmacology; D004594:Electrophysiology; D005971:Glutamates / Q000494:pharmacology; D008024:Ligands; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D010716:Phosphatidylinositols / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000378:metabolism; D012601:Scopolamine / Q000494:pharmacology; D013237:Stereoisomerism; D013574:Synaptosomes / Q000378:metabolism
D001581:Benzothiadiazines; D005971:Glutamates; D008024:Ligands; D010716:Phosphatidylinositols; D011810:Quinoxalines; D018091:Receptors, AMPA; D011976:Receptors, Muscarinic; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C091420:IDRA 21; D002740:Chlorothiazide; D012601:Scopolamine; D003981:Diazoxide; D000525:Alprazolam