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Nitric oxide‐donating properties of mesoionic 3‐aryl substituted oxatriazole‐5‐imine derivatives
Author(s) -
Kankaanranta H.,
Rydell E.,
Petersson A.S.,
Holm P.,
Moilanen E.,
Corell T.,
Karup G.,
Vuorinen P.,
Pedersen S.B.,
Wennmalm ÅR.,
MetsäKetelä T.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15204.x
Subject(s) - snap , zaprinast , chemistry , imine , nitric oxide , mesoionic , stereochemistry , nitrite , medicinal chemistry , biochemistry , organic chemistry , nitrate , cyclic gmp , computer graphics (images) , computer science , catalysis
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 NO‐donors 3‐morpholino‐sydnonimine (SIN‐1) and S‐nitroso‐ N ‐acetylpenicillamine (SNAP). 2 GEA 3162, GEA 3175, SIN‐1 and SNAP inhibited adenosine 5′‐diphosphate‐induced platelet aggregation (IC 50 values 0.18, 0.39, 3.73 and 2.12 μ m , respectively). All four compounds induced a dose‐dependent 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 μ m ) and inhibited 38–97% by oxyhaemoglobin (10–45 μ m ). 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‐1 and SNAP (100 μ m ) produced 50–70 μ m NO 2 − +NO 3 − as determined by high performance liquid chromatography. The release of NO and NO 2 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‐1 and SNAP release nitric oxide.