Diazoxide series

Replacement of the sulfonamide group at the 7 position by chlorine markedly diminishes the diuretic effect in this series. One such compound, diazoxide (169), exhibits instead potent anti-... 

A series of 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1 -dioxides (168a-j) that are related to diazoxide (396) (a compound which induces hyperglycemia in vivo through decreased insulin secretion and is a potent pancreatic KATP channel opener) and pinacidil (397) were prepared and tested as inhibitors of insulin release from rat pancreatic islets. Of the compounds tested, BPDZ 44 (168g) was chosen for further study as a potential probe for KATP channels. The compounds tested were the most powerful inhibitors of insulin release reported at that time <93JMC32li>. 

This topic has been reviewed both generally [9], and specifically for variation in the benzopyran nucleus [10]. SARs have also formed part of several comprehensive and useful reports and reviews [11-15], while full details of lead and development KCAs are regularly updated in a useful compilation [16] devoted to modulators of K channels. Hence, this section will address recent advances, and those previously reported [9, 10], where further detail is now available. These are best presented in terms of the different series of KCAs based on the prototype molecules, cromakalim (1), RP 49356 (4), pinacidil (6), and nicorandil (7) that, together with the older compounds, minoxidil sulphate (8) and diazoxide (9), now recognized as KCAs, illustrate the widening range of structural types of this classification... 

As desensitisation is a prominent feature of AMPA receptors, a plant lectin, concanavilin A, previously shown to block desensitisation of insect glutamate receptors [54], was tested and found to enhance AMPA and kainate responses on hippocampal [43, 66], retinal [67] and dorsal root ganglion (DRG) [68] neurones. More recently, a series of benzothiazides including diazoxide and cyclothiazide, were shown to reduce glutamate receptor desensitisation and hence increase AMPA responses on hippocampal [69, 70] and cortical [71] neurones. As will be discussed below, it has become clear that concanavilin A and cyclothiazide act selectively on rapidly inactivating kainate and AMPA responses respectively. 

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