(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide: (S18986-1) a positive modulator of AMPA receptors enhances (S)-AMPA-mediated [3H]noradrenaline release from rat hippocampal and frontal cortex slices

Eur J Pharmacol. 2000 Aug 4;401(2):145-53. doi: 10.1016/s0014-2999(00)00433-7.


The present study describes the effect of (S)-2,3-dihydro-[3, 4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S18986-1), a positive allosteric modulator of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors with cognitive-enhancing effects, on (S)-AMPA-induced [3H]noradrenaline release in rat hippocampal and frontal cortex slices. (S)-AMPA significantly increased [3H]noradrenaline release in rat hippocampus and frontal cortex slices, whereas S18986-1 (3-1000 microM) alone, was inactive. However, S18986-1 between 30 and 1000 microM potently enhanced (+200%) (S)-AMPA-mediated [3H]noradrenaline release in both hippocampal and frontal cortex slices. The capacity of S18986-1 to potentiate [3H]noradrenaline release was specific for AMPA receptors as S18986-1 failed to potentiate either kainate and N-methyl-D-aspartate (NMDA)-mediated release of [3H]noradrenaline in rat hippocampal slices. Moreover, 1, 2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX) and 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-3, 4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI-53655) but not (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine ((+)-MK-801), inhibited (S)-AMPA and S18986-induced stimulation of (S)-AMPA-mediated [3H]noradrenaline release. In addition, S18986-1-induced stimulation of (S)-AMPA-evoked [3H]noradrenaline release was markedly attenuated in the presence of tetrodotoxin (1 microM) and in Ca(2+)-free buffer. S18986-1 enhanced (S)-AMPA-mediated [3H]noradrenaline release to a greater extent than its corresponding (R)-enantiomer S19024-1 and racemic mixture S17951-1. However, positive allosteric modulators of AMPA receptors such as aniracetam failed to potentiate AMPA-mediated noradrenaline release in hippocampal slices, whereas cyclothiazide potently enhanced (S)-AMPA-mediated [3H]noradrenaline release. These results suggest that the capacity of S18986-1 to enhance AMPA receptor-mediated release of noradrenaline in rat hippocampus and frontal cortex, could contribute to the cognition enhancing mechanisms of S18986-1.

MeSH terms

  • Animals
  • Benzodiazepines / pharmacology
  • Benzothiadiazines / chemistry
  • Benzothiadiazines / pharmacology*
  • Calcium / pharmacology
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Excitatory Amino Acid Antagonists / pharmacology
  • Frontal Lobe / drug effects*
  • Frontal Lobe / metabolism
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • In Vitro Techniques
  • Male
  • Norepinephrine / metabolism*
  • Pyrrolidinones / pharmacology
  • Quinoxalines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, AMPA / drug effects*
  • Receptors, AMPA / physiology
  • Stereoisomerism
  • Tetrodotoxin / pharmacology
  • Tritium
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology*


  • Benzothiadiazines
  • Excitatory Amino Acid Antagonists
  • Pyrrolidinones
  • Quinoxalines
  • Receptors, AMPA
  • S18986-1
  • Tritium
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • Benzodiazepines
  • GYKI 53655
  • Tetrodotoxin
  • aniracetam
  • Dizocilpine Maleate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • cyclothiazide
  • Calcium
  • Norepinephrine