Synthesis of Modified 4H‐1,2,4‐Benzothiadiazine‐1,1‐dioxides and Determination of their Affinity and Selectivity for Different Types of K_ATP Channels

Abstract

4H-1,2,4-Benzothiadiazine-1,1-dioxides with various substituents in positions 3, 5, and 7 were synthesized and tested as K(ATP) channel agonists in artificial cell systems (CHO cells transfected with SUR1/Kir6.2, and HEK 293 transfected with SUR2B/Kir6.1) as model systems for insulin-secreting pancreatic beta-cells and for smooth muscle cells, respectively. The effects of agonists were tested in intact cells using DiBAC4(3) [bis-(1,3-dibarbituric acid)trimethine oxanol] as a membrane potential dye, and the results compared with their binding affinity for the SUR2B-type K(ATP) channels using the radioligand [(3)H]P1075. Compounds with cycloalkyl and (cycloalkyl)methyl side chains in position 3 had higher affinities towards the SUR2B/Kir6.1 receptor compared with the parent compound diazoxide (1 a). Compounds with bulky, nonpolar residues in position 3 exhibited remarkable selectivity for SUR2B-type K(ATP) channels. The compound substituted with a bulky (1-adamantyl)methyl residue exhibited micromolar affinity and activity on SUR2B-type K(ATP) channels without being able to activate the SUR1-type K(ATP) channels.

Impact of the Nature of the Substituent at the 3-Position of 4H-1,2,4-Benzothiadiazine 1,1-Dioxides on Their Opening Activity toward ATP-Sensitive Potassium Channels

“…However, and according to recent published data obtained with a series of 7-chloro-3-cycloalkyl-4H-1,2,4-benzothiadiazine 1,1-dioxides, 25 it was expected that a substituent more bulky than an isobutyl chain (i.e., a cyclohexyl chain) at the 3-position should induce a loss of activity on SUR1-type K ATP channels (pancreatic β-cell type channels), while keeping a high level of activity on the SUR2B-type K ATP channels (smooth muscle cell type channels). 25 The less vasorelaxant compound among the selected benzothiadiazines (see Table 2) was the 3-alkylamino-substituted benzothiadiazine dioxide 4, being also the most selective toward the pancreatic tissue.…”

“…: diazoxide). However, and according to recent published data obtained with a series of 7-chloro-3-cycloalkyl-4 H -1,2,4-benzothiadiazine 1,1-dioxides, it was expected that a substituent more bulky than an isobutyl chain (i.e., a cyclohexyl chain) at the 3-position should induce a loss of activity on SUR1-type K ATP channels (pancreatic β-cell type channels), while keeping a high level of activity on the SUR2B-type K ATP channels (smooth muscle cell type channels) …”

Synthesis of Benzofuran, Benzothiophene, and Benzothiazole‐Based Thioamides and their Evaluation as KATP Channel Openers

“…. [12] Finally, carbamate 13 represents a swap of the lipophilic and hydrophilic regions relative to the benzofurans 10; this dramatic modification is deleterious to the affinity (Entry 25).…”

“…[12] Therefore, we were also interested to determine the selectivity of the current compounds. However, with no agonist radioligands for SUR1-type K ATP channels yet available which would permit the determination of K D values for SUR1-agonists, the selectivity of compounds for different channel types must be measured by functional methods.…”

Tandem Protocol for the Synthesis of 3‐Acyl Benzothiadiazine 1,1‐Dioxides

“…[11] Moreover, they have been employed as moderate efficacy diuretic, [12] alkaline phosphatase inhibitor, [13] phosphodiesterase inhibitor, [14] 5-HT 1A receptor agonist, [15] HIV-1 infection antagonist [16] and K ATP channel modulator. [17] Hence, several methods have been reported for their synthesis.…”