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 NO-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 (I DRA 21), which attenuates the rapid autodesensitization of no-2,3-dihy dro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA)-selective glutamat e receptors and increases excitatory synaptic strength, improves cogni tion (learning and memory), as revealed by its ability to improve perf ormance in water maze and passive avoidance tests in rats. Normal rats trained to (15-20 sec) reach the exit platform rapidly in a water maz e that included four incorrect choices were given oral IDRA 21 (4-120 mu mol/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 th at received the vehicle. Moreover, oral IDRA 21 (ED(50) = 7.6 mu M) at tenuated the performance impairment induced by the AMPA receptor antag onist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (F) quinoxaline in the wa ter maze test. in this test and in a passive avoidance test, the perfo rmance impairment elicited by alprazolam, a full allosteric modulator at gamma-aminobutyric acid-A receptors, or by scopolamine, a competiti ve muscarinic receptor antagonist, was also reduced by oral administra tion of IDRA 21 (ED(50) = 13 and 108 mu mol/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 molecu le; the two stereoisomers were isolated and studied behaviorally. Only the (+) form was found to be behaviorally active. These results indic ate that IDRA 21 given orally to rats presumably crosses the blood-bra in barrier and acts stereoselectively on specific receptors that were operative during this behavioral procedure. Because the activity of ID RA 21 on rat cognition tests appears to be related to its ability to p otentiate AMPA-activated currents, one can suggest that IDRA 21 improv es cognition by acting on a stereoselective site of AMPA receptor that is operative in attenuating the rapid autodesensitization of these re ceptors.