Malchenko O. Search for new analgesics among N-aryl(hetaryl)-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide and their structurally similar analogues (experimental study)

For the first time in a model of carrageenan edema in rats, pharmacological screening was performed among a large group of N-aryl(hetaryl)-substituted 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides, their close structural analogs, and some polymorphic modifications. The most active substances were identified as a potential analgesic and anti-inflammatory remedies. The most active and safe was N- (4-methoxybenzyl) -4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide (compound NI-9), which in these respects surpassed the reference drugs diclofenac and meloxicam. According to the results of molecular docking, a high degree of affinity and probability of realization of analgesic and anti-inflammatory effects of this compound due to inhibition of the enzyme COX-2 was predicted. New data on the analgesic activity of the compound NI-9 in models of pain syndromes of somatic, visceral and neuropathic origin were obtained. Studies of the ulcerogenic potential of the compound have shown its high level of safety in the gastrointestinal tract, which surpasses meloxicam. Scientific data on the molecular mechanisms of the damaging effect of benzothiazine-3-carboxylic acid derivatives on the gastrointestinal tract, which included depressant effects on different levels of gastric protection, have been supplemented. NI-9 was probably inferior to meloxicam in terms of its effect on lipid and protein peroxidation and mucus production, while these compounds were comparable in terms of its effect on the phospholipid bilayer of gastric mucosal membranes. NI-9, in contrast to meloxicam, did not cause changes in nitrates and nitrites and H2S levels in the gastric mucosa, did not affect the sensitivity of the mesenteric arteries to the vasorelaxant effect of H2S. It has been shown for the first time that the opioidergic system is not involved in the mechanisms of antinociceptive action of NI-9, but the participation of alpha1- and alpha2-adrenoceptors, cholinergic, dopamine and partially NMDA-receptors has been proven.