Nitric oxide‐donating properties of mesoionic 3‐aryl substituted oxatriazole‐5‐imine derivatives

Abstract

1 The nitric oxide (NO)-releasing properties of two new mesoionic 3-aryl substituted oxatriazole-5-imine derivatives (GEA 3162 and GEA 3175) were characterized and compared with the known NOdonors 3-morpholino-sydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP). 2 GEA 3162, GEA 3175, SIN-i and SNAP inhibited adenosine 5'-diphosphate-induced platelet aggregation (IC50 values 0.18, 0.39, 3.73 and 2.12 gM, respectively). All four compounds induced a dosedependent and more than 4 fold increase in cyclic GMP in platelets. The increase in cyclic GMP concentration was potentiated more than 1.5 fold by a phosphodiesterase inhibitor, zaprinast (10 gM) and inhibited 38-97% by oxyhaemoglobin (10-45 gM).3 All of the four compounds studied converted oxyhaemoglobin to methaemoglobin and formed a paramagnetic NO-haemoglobin complex. All but GEA 3175 formed nitrite and nitrate in phosphate buffer. During a 40 min incubation, GEA 3162, SIN-I and SNAP (100 pM) produced 50-70 gM NO2-+ NO3-as determined by high performance liquid chromatography. The release of NO and NO2 by GEA 3175 was increased 140 fold in the presence of human plasma (0.14 and 19.7 ppb in the absence and presence of 1% human plasma, respectively) as analyzed by ozone chemiluminescence. 4 The results suggest that the mesoionic 3-aryl substituted oxatriazole-5-imine derivatives GEA 3162 and GEA 3175 as well as SIN-l and SNAP release nitric oxide.

Ca2+ Pool Emptying Stimulates Ca2+ Entry Activated by S-Nitrosylation

“…1A. An unusually lipophilic NO-releasing agent, GEA3162, was recently characterized as a highly effective NO donor in vitro and in mediating the actions of NO on intact cells (27,28). Although lipophilic, this mesoionic 3-arylsubstituted oxatriazole-5-imine derivative is sufficiently amphipathic that it may preferentially localize to donate NO in close proximity to the membrane surface.…”

“…These results indicate operation of an important and potentially widespread NO donor-induced Ca 2ϩ entry mechanism that undergoes striking stimulation by pool emptying. Entry is activated at M NO donor concentrations that may correspond to NO levels in the physiological nM range (27,28).…”

“…4-VP and NEM are both membrane permeant. Of many NO donors tested, GEA3162 and the close structural analogue, GEA5024 (27), were most effective in activating Ca 2ϩ entry. As mentioned above, these compounds differ from other NO donors in being lipophilic enough to penetrate the membrane; yet by virtue of weak charge on the oxatriazole ring, they may be sufficiently amphipathic to selectively donate NO at the surface of the membrane in the vicinity of reactive thiols of the entry channel or an associated protein.…”

Endothelium-Derived Nitric Oxide Contributes to the Vasorelaxant Response Induced by Mesoionic 2-(4-Chlorophenyl)-3-methyl-4-(4-methoxyphenyl)-1;3-thiazolium-5-thyolate (CMMTT) in Rats

“…NO-donating properties were reported for substituted mesoionic oxatriazole-5-imine derivatives (3,20,21). It is well reported in the literature that L-NOHA (48) and other NO-donors can also induce NOS-independent relaxation in endothelium-denuded arteries and that this relaxation involves the NO-cGMP pathway (48,49).…”

“…Some effects described for these compounds are intimately related to the presence of specific substituent groups on the ring (3,5) or nitric oxide (NO)-donating properties from their molecular structures (3,20,21). Among the mesoionic compounds, and their derivatives, that have been extensively studied are the following compounds of the sydnone family: sydnone (1,2,3-oxadiazolium-5 olate), sydnonimine (1,2,3-oxadiazolium-5 amide), and the oxatriazolium, all of them bearing =N-NO bond, are the most active on the cardiovascular system since they present NO-donor properties (2,21,22).…”