4H-1,2,4-PYRIDOTHIADIAZINE 1,1-DIOXIDES AND 2,3-DIHYDRO-4H-1,2,4-PYRIDOTHIADIAZINE 1,1-DIOXIDES CHEMICALLY RELATED TO DIAZOXIDE AND CYCLOTHIAZIDE AS POWERFUL POSITIVE ALLOSTERIC MODULATORS OF (R AMINO-3-(3-HYDROXY-5-METHYLISOXAZOL-4-YL)PROPIONIC ACID RECEPTORS - DESIGN, SYNTHESIS, PHARMACOLOGY, AND STRUCTURE-ACTIVITY-RELATIONSHIPS/

A series of 4H-1,2,4-pyridothiadiazine 1,1-dioxides and 2,3-dihydro-4H -1,2,4-pyridothiadiazine 1,1-dioxides bearing various alkyl and aryl s ubstituents on the 2-, 3-, and 4-positions was synthesized and tested as possible positive allosteric modulators of the (R/S)-2-amino-3-(3-h ydroxy-5-methylisoxazol-4- yl)propionic acid (AMPA) receptors. Many co mpounds were found to be more potent than the reference compounds diaz oxide and aniracetam as potentiators of the AMPA current in rat cortex mRNA-injected Xenopus oocytes. The most active compound, hyl-2,3-dihy dro-4H-pyrido[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (31b), revealed an in vitro activity on Xenopus oocytes not far from that of cyclothiazid e, the most potent allosteric modulator of AMPA receptors reported to date. Moreover, 31b, but not cyclothiazide, was found to potentiate th e duration and the amplitude of the excitatory postsynaptic field pote ntials induced by electric stimulation in rat hippocampal slices. Such an effect could indicate, for 31b, but not for cyclothiazide, a possi ble interaction with postsynaptic AMPA receptor binding sites located on hippocampal CA1 neurons. Structure-activity relationships indicated that the structural requirements responsible for a biological activit y on AMPA receptors are different from those responsible for an inhibi tory activity on the insulin releasing process (putative ATP-sensitive K+-channel openers). For instance, 31b and other related dihydropyrid othiadiazines were found to be ineffective as inhibitors of insulin re lease from rat pancreatic B-cells, in contrast to diazoxide and known pyridothiadiazines reported as ATP-sensitive K+-channel openers. Conve rsely, the pyridothiadiazines active on B-cells were found to be ineff ective as potentiators of the AMPA currents in Xenopus oocytes. Thus, 31b appeared to be more specific than diazoxide as an AMPA receptor mo dulator. This compound may be considered as a new pharmacological tool , different from diazoxide and cyclothiazide, for studying AMPA recept ors. Moreover, 31b can also constitute a new therapeutic agent for the treatment of cognitive disorders.