7-Chloro-3-methyl-3,4-dihydro-2 H -1,2,4-benzothiadiazine S , S -dioxide: A partial modulator of AMPA receptor desensitization devoid of neurotoxicity

Abstract

In cerebellar granule neurons of neonatal rats micromolar concentrations of 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide (IDRA-21) and cyclothiazide, two negative modulators of the spontaneous agonist-dependent rapid desensitization of ␣-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA)-gated ion channels, facilitate AMPA receptor function by increasing the content of free cytosolic Ca 2؉ as measured by single-cell fura-2 acetoxymethyl ester (Fura-2) Ca 2؉ -dependent f luorescence and intracellular Na ؉ measured with the sodium-binding bezofuran isophthalate acetoxymethyl ester f luorescence indicator. IDRA-21 increases intracellular Na ؉ transient with a threshold (5 M) that is Ϸ10 times higher and has an intrinsic activity significantly lower than that of cyclothiazide. By virtue of its low intrinsic activity, IDRA-21 elicits a free cytosolic Ca 2؉ transient increase that is shorter lasting than that elicited by cyclothiazide even when the drug is left in contact with cultured granule cells for several minutes. Additionally, while dose dependently, 5-25 M cyclothiazide in the presence of AMPA is highly neurotoxic, IDRA-21 (up to 100 M) is devoid of neurotoxicity. The neurotoxicity elicited by cyclothiazide persists in the presence of dizocilpine (an antagonist of N-methyl-D-aspartate-selective glutamate receptors) but is blocked by 2,3-dihydroxy-6-nitrosulfamoylbenzo[f]quinoxaline (a competitive AMPA receptor antagonist) and the 1-(aminophenyl)-4-methyl-7,8-methylendioxy-5H-2,3-benzodiazepine (GYKI 52466; a noncompetitive AMPA receptor antagonist). Since the doses of IDRA-21 that enhance cognitive processes in rats and monkeys are several orders of magnitude lower than those required to elicit marginal neurotoxicity in cultured neurons, it can be surmised that IDRA-21 is a potent cognition-enhancing drug virtually devoid of neurotoxic liability because it acts as a partial negative allosteric modulator of AMPA receptor desensitization.

Role of desensitization of AMPA receptors on the neuronal viability and on the [Ca2+]i changes in cultured rat hippocampal neurons

“…It was found that AMPA exposure for short or long time periods produced little or no toxicity (Deupree et al . 1996; May & Robison, 1993; Impagnatiello et al . 1997; Ohno et al .…”

Studies of enantiomerization of chiral 3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide type compounds

“…[4][5][6] The observed cognition-enhancing effect of (±)IDRA21, which is more potent in experimental animals than aniracetam, suggests the potential applicability of this drug in the treatment of attention disorders in children and in senile dementias, including early stage Alzheimer disease. 7 (±)IDRA 21, like cyclothiazide and other chiral diuretics of the benzothiadiazine type, contains a stereogenic carbon atom in the benzothiadiazine ring. As stereoisomers often show different pharmacological activities, it is of interest to investigate the biological properties of each individual enantiomer.…”

Copper‐Catalyzed Synthesis of 1,2,4‐Benzothiadiazine 1,1‐Dioxide Derivatives by Coupling of 2‐Halobenzenesulfonamides with Amidines

“…[3] Cyclothiazid [4] and IDRA 21 [5] have been demonstrated to be among the most potent compounds that enhance synaptic transmission by removal of AMPA receptor desensitization. [6] Some cyclothiazide derivatives exhibit physico-chemical characteristics which should facilitate the crossing of the blood-brain barrier and have potential application in the treatment of attention disorders in children as well as senile dementias. In addition, some of the benzothiadiazine derivatives (such as A in Figure 1) have also been shown to possess antiviral activities [7] particularly against human herpes virus 6 (HHV-6), human cytomegalovirus (H-CMV) and Varicella-Zoster virus (VVZ), and they have been also reported as heterocyclic inhibitors of PDE7 with concurrent inhibitory activity at PDE4 and PDE3.…”