engleski

7-Chloro-3Methyl-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-Methil-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 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 that received the vehicle. Moreover, oral IDRA 21 (ED(50) = 7.6 mu M) 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 (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 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.

IDRA 21 ; Benzothiadiazine derivative ; Cognition ; AMPA

U ovome multi-eksperimentalnom projektu vršena su istraživanja u kojoj mjeri kemijska derivativna tvar benzodiazina (IDRA 21) poboljšava kognitivnu moć kod životinja. Ustanovljeno je da se IDRA 21 pokazuje učinkovitim u deblokaciji receptora neurotransmitera acetikolina koji je odgovoran za pamćenje. Štoviše utvrđeno je da IDRA 21 djeluje dvadeset do trideset puta učinkovitije od poznatog aniracetama. Rezultati istraživanja ukazuju na to da oralna primjena IDRE 21 penetrira kroz krvno moždanu barijeru, te djeluje stereoselektivno na specifične receptore selektivnih glutamatnih AMPA receptora, što dovodi do auto-desentizacije tih receptora. Ovaj rad je naišao na veliko zanimanje neuro-biologa i farmakologa te je kemijska supstanca IDRA 21 patentirana te je ušla u proces kliničkog testiranja za moguću primjenu na ljudima.