Antiplatelet activity of 2-(6-carboxyhexyl)-3-n-hexylcyclohexylamine (IBI P-05006), a thromboxane receptor antagonist.
2-(6-Carboxyhexyl)-3-n-hexylcyclohexylamine (IBI P-05006) is a molecule with cytoprotective and antisecretory actions. Since its chemical structure resembles that of the prostanoid nucleus of thromboxane (Tx) A2, the possibility of antiplatelet activity was investigated. The aims of our study were to evaluate a possible inhibitory effect of IBI P-05006 on in vitro platelet aggregation induced by different stimuli and to characterize its mechanism of action. For this purpose, selected mechanisms of platelet function were evaluated. IBI P-05006 inhibited platelet aggregation induced by arachidonic acid or U46619, at concentrations ranging from 0.4 to 4 microM, dose dependently, without interfering with arachidonic acid metabolism. The possibility that the compound acts through adenylate cyclase stimulation was ruled out by measurement of cAMP levels, which were not increased. Receptor binding studies indicated competitive inhibition by IBI P-05006 of the binding of the ligand [3H]SQ29548 to the TxA2/(prostaglandin) PG-cyclic endoperoxides receptor with IC50 in the range of concentrations active on platelet aggregation. In conclusion, IBI P-05006 inhibits in vitro human platelet aggregation through a specific mechanism of competition for the TxA2/PG-cyclic endoperoxides receptor.
Rotondo
S
S
Giulio Bizzozero Laboratory of Platelet and Leucocyte Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.
De Gaetano
G
G
Cerletti
C
C
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000242:Cyclic AMP / Q000097:blood; D003514:Cyclohexylamines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000378:metabolism; D066298:In Vitro Techniques; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D011869:Radioligand Assay; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D003514:Cyclohexylamines; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; C078016:2-(6'-carboxyhexyl)-3-n-hexylcyclohexylamine; D016718:Arachidonic Acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D000242:Cyclic AMP