Thromboxane A2 receptor

Drugs that target other sites of platelet action include thromboxane synthetase inhibitors, serotonin or 5-hydroxytryptamine (5-HT2) receptor blockers, and thromboxane A2 receptor blockers, in addition to cyclooxygenase inhibitors and prostaglandin analogues. 

Hirata, T., Ushikubi, E., Kakizuka, A., Okuma, M., and Narumiya, S. (1996) Two thromboxane A2 receptor isoforms in human platelets. Opposite coupling to adenylyl cyclase with different sensitivity to Arg60 to Leu mutation. J. Clin. Invest. 97,949-956. 

Thromboxane A2 receptor TBXA2R Agonism Vaso-, bronchoconstriction. platelet aggregation, myocardial ischemia, heart failure. Antagonism could cause bleeding by inhibiting platelet aggregation. 

M. Hirata, Y. Hayashi, F. Ushikubi, Y. Yokota, R. Kageyama, S. Nakanishi, S. Narumiya, Cloning and expression of cDNAfora human thromboxane A2 receptor. Nature 349 (1991) 617. 

M. Takasuka, M. Kishi, M. Yamakawa, FTIR spectral study of intramolecular hydrogen bonding in thromboxane A2 receptor agonist (U-46619), prostaglandin (PG)E2, PGD2, PGF2.alpha., prostacyclin receptor agonist (carbacyclin) and their related compounds in dilute carbon tetrachloride solution Structure-activity relationships, J. Med. Chem. 37 (1994) 47. 

Molecular pharmacology and therapeutic potential of thromboxane A2 receptor antagonists, 25, 173... 

Li Z, Zhang G, Le Breton GC, Gao X, Malik AB, Du X. Two waves of platelet secretion induced by thromboxane A2 receptor and a critical role for phosphoinositide 3-kinases. J Biol Chem 2003 278 30,725-30,73 I. 

Antiplatelet and antithrombotic drugs Aspirin, dipyridamole, ticlopidine Thromboxane A2 receptor antagonists—vapiprost and solutroban... 

Serruys FW, Rutsch W Heyndrickx GR, et al. Prevention of restenosis after percutaneous transluminal coronary angioplasty with thromboxane A2-receptor blockade. A randomized, double-blind, placebo-controlled trial. Coronary Artery Restenosis Prevention on Repeated Thromboxane-Antagonism Study (CARPORT). Circulation 1991 84(4) 1568-1580. 

Synthesis of quinone derivatives containing saturated O-heterocyclic substituents as 5-lipoxygenase inhibitors and antagonists of thromboxane A2 receptors 92YGK786. 

III. Short-Term Treatment of Ocular Hypertension A. Thromboxane A2 Receptor Agonists... 

Fluoro prostaglandin, (IV), PGF2a analogs effective as thromboxane A2 receptor agonists were prepared by Klimko (3) and used in the treatment of glaucoma and ocular hypertension. 

Thromboxane A2 receptor antagonists consisting of 2-decarboxy-2-phosphinico prostaglandins (V), and prostamide derivatives, (VI), prepared by deLong (4) and Krauss (5), respectively, and were used in glaucoma therapy. 

A recent method called 4D-QSAR (63) builds and optimizes a set of relevant 3D-pharmacophores for a specific target and effectively samples the available conformational space and identifies a sound QSAR in terms of binding mode of each compound examined. The method has been successfully validated in the design and virtual screening of libraries aimed towards the thromboxane A2 receptor (64) and glycogen phosphorylase b (65, 66) both examples have produced virtual hits which, once prepared and tested on the target, were confirmed as novel bioactive compounds. 

On the basis of these results it has been suggested that electronic factors— Hammett s sigma (a) constant, dipole moment (/z) and Swain and Lupton s polarity (F)—are crucial for the antithrombotic activity of these compounds. Interestingly, in all the active compounds presented in Fig. 24 the arrangement of substituents around the thiazole skeleton is different from one another. This has further widened the scope of this skeleton in the exploration of potential platelet aggregation inhibitors and thromboxane A2 receptor antagonist. 

Takahashi K, Nammour TM, Fukunaga M, Ebert J, Morrow JD, Roberts LJ Jr, Hoover RL, Badr KF. Glomerular actions of a free radical-generated novel prostaglandin, 8-epi-prostaglandin F2 alpha, in the rat. Evidence for interaction with thromboxane A2 receptors. J. Clin. Invest. 1992 90 136. 

Allan Cl, Halushka PV. Characterization of human peripheral blood monocyte thromboxane A2 receptors. J Pharmacol Exp Ther 1994 270 446-52... 

Gresele P, Dedomyn H, Amout J, N nci GG, V rmyl n J. Characterization of N,N -t>is(3 pioolyl)-4-methoxy-isophthalamide (piootamide) as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets. HircmibHaemost 1989 61 479-84... 

Roald HE, Barstad RM, Engen A, Kierulf P, Skjorten F, Sakariassen KS. HN-1 ISOO-anovel thromboxane A2 receptor anb onist with antithrondwtic activity in humans at arterid blood flow oonditimis. Thrond> Haemost 1994 71 103-9... 

Silicic DD, Wencd-Drake ID, Parise LV. Ras activation in platelets after stimulation of the thrombin receptor, thromboxane A2 receptor or protein kinase C. Biodiem J1997 321 S2S-S30. 

SHENKER A, GOLDSMITH P, UNSON C, SPIEGEL A (1991) The G jn-otein coupled to the thromboxane A2 receptor in human platdets is a member of the novd G, family. J.BioLChem., 266,9309-9313. 

Scheurlen M, Kirchner M, and Clemens MR., and Jasdionek K. (1993). Fish oil prq>arations ridi in docosahexaenoic acid modify platelet responsiveness to prostaglandin-endoperoxide/thromboxane A2 receptor agonists. Biochem. Pharmacol. 46,245-249. 

Defects in platelet-agonist interaction are exemplified by patients with impaired responses because of an abnormality at the level of platelet surface receptors for a specific agonist. Such receptor defects have been documented for epinephrine, collagert, ADP, and thromboxane A2. Hirata et al (21) have described an Arg 60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder. Evidence has been... 

In a study ot the ettects ot aspirin 325 mg/day, both acute (4 hours atter the dose) and chronic (6 weeks), in 62 patients with mild to moderate heart tailure taking enala-pril (more than 10 mg/day tor at least 3 months), there were no significant changes in mean arterial pressure or in forearm blood flow and vascular resistance measured by venous plethysmography (112). In another arm ot the study the same results were observed with itetroban 250 mg/day, a thromboxane A2 receptor antagonist. 

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