7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide (IDRA 21), a congener of aniracetam, potently abates pharmacologically induced cognitive impairments in patas monkeys.

We report here on the ability of IDRA 21 and aniracetam, two negative allosteric modulators of glutamate-induced DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization, to attenuate alprazolam-induced learning deficit in patas monkeys working in a complex behavioral task. In one component of a multiple schedule (repeated acquisition or "learning"), patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four discriminative stimuli (geometric forms or numerals). In the other component (performance) the four-response chain was the same each session. The response chain in each component was maintained by food presentation under a fixed-ratio schedule. When alprazolam (0.1 or 0.32 mg/kg p.o.) was administered alone, this full allosteric modulator of gamma-aminobutyric acid type A (GABAA) receptors produced large decreases in the response rate and accuracy in the learning component of the task. IDRA 21 (3 or 5.6 mg/kg p.o.) and aniracetam (30 mg/kg p.o.) administered 60 min before alprazolam, having no effect when given alone, antagonized the large disruptive effects of alprazolam on learning. From dose-response studies, it can be estimated that IDRA 21 is approximately 10-fold more potent than aniracetam in antagonizing alprazolam-induced learning deficit. We conclude that IDRA 21, a chemically unrelated pharmacological congener of aniracetam, improves learning deficit induced in patas monkeys by the increase of GABAergic tone elicited by alprazolam. Very likely IDRA 21 exerts its behavioral effects by antagonizing AMPA receptor desensitization.

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.

Modulation of AMPA/kainate receptors by analogues of diazoxide and cyclothiazide in thin slices of rat hippocampus.

Among the non-NMDA (non-N-methyl-D-aspartic acid) glutamate receptors, the AMPA (alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid) selective receptors are characterized by a fast occurring desensitization. We and others have searched for specific modifiers of the rapid desensitization of AMPA responses in hippocampal slices using the patch-clamp technique. Aniracetam (1-(4-methoxybenzoyl)-2-pyrrolidinone) and diazoxide (7-chloro-3-methyl-2H-1,2,4-benzo-thiadiazine 1,1-dioxide) (1 mM) increased glutamate-activated currents recorded from voltage-clamped CA1 pyramidal neurons in presence of 5 microM MK-801 (dizocilpine; 10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine) by 2.5 fold. Cyclothiazide (3-bicyclo[2.2.1]hept-5-en-2-yl-6-chloro-3,4-dihydro-2H-1,2,4-benzoth ia diazine-7-sulfonamide 1,1-dioxide) (100 microM), a chemical congener of diazoxide, completely removed the desensitization of the AMPA response measured with fast application in excised outside-out patches. At this concentration cyclothiazide produced an 18 fold enhancement of the glutamate current. Eighteen diazoxide analogues (2H-1,2,4-benzothiadizines: IDRA 2-19) were then tested but none of them was as effective as diazoxide. Three analogues of cyclothiazide (3,4-dihydro-2H-1,2,4-benzothiadiazines: IDRA 20-22) were also tested and none of them were as potent as the parent compound. However, IDRA 21 produced a response 3 times larger than diazoxide. Moreover, while cyclothiazide and diazoxide potentiated kainate responses for all the doses that decreased AMPA receptor desensitization, IDRA 21, similarly to aniracetam, inhibited AMPA receptor desensitization preferentially. These results suggest that similarly to NMDA receptors the structure of AMPA receptors may include a center that regulates desensitization.