Repurposing an old drug for a new use: glybenclamide exerts antiplatelet activity by interacting with the thromboxane A(2) receptor.
OBJECTIVE
To investigate the potential antagonistic activity of the antidiabetic agent glybenclamide for the human platelet thromboxane A(2) receptor (abbreviated as TPR).


METHODS
Platelets were obtained from healthy donors. Aggregation studies were performed in a model 700 aggregometry system. Radioactivity was counted in a Beckman LS 6000 liquid scintillation counter and calcium imaging was performed using an LS50B PerkinElmer Fluorescence Spectrometer.


RESULTS
It was found that glybenclamide: 1) inhibited aggregation induced by the TPR agonist U46619 (IC(50)=2.3+/-0.31 micromol/L) and by the thromboxane A(2) precursor arachidonic acid (IC(50)=2.6+/-0.24 micromol/L); 2) displaced SQ29,548 from its binding sites on platelets; 3) lacked any detectable effects on aggregation stimulated by ADP, or the thrombin receptor activating-peptide 4; 4) blocked calcium mobilization induced by U46619, but not by ADP; and 5) failed to raise cAMP levels.


CONCLUSIONS
The findings indicate that glybenclamide exerts inhibitory effects on platelets by interacting with TPR. Thus, glybenclamide or a rationally designed derivative has the potential to serve as an antithrombotic agent.
Ting
Harold J
HJ
Department of Pharmaceutical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
Murray
Wallace J
WJ
Khasawneh
Fadi T
FT
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D001665:Binding Sites; D001792:Blood Platelets / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000097:blood; D005231:Fatty Acids, Unsaturated; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000187:drug effects* / Q000378:metabolism; D012588:Scintillation Counting; D013050:Spectrometry, Fluorescence
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010975:Platelet Aggregation Inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D000242:Cyclic AMP; D005905:Glyburide; D002118:Calcium