title: Pharmacological evidence for thromboxane receptor heterogeneity--implications for the eye.
abstract: The pharmacological activity of two novel thromboxane A2 (TxA2)-mimetics, AGN191976 and AGN192093, was investigated in vitro, using standard organ bath assays and human platelets, to determine potency and selectivity at various prostanoid (PG-) receptors. The effects of these compounds on intraocular pressure in Beagle dogs were then compared with U-46619, a widely employed and structurally different TP-receptor agonist. AGN191976 and AGN192093 were highly potent TP-receptor agonists in the rat aorta (EC50 of 0.32 and 1.3 nM, respectively) and human myometrium. Both compounds were approximately 10 to 50 fold more potent than U-46619. These contractile responses could be blocked with a potent TP-receptor antagonist, SQ29548. In human platelets, AGN191976 (EC50 = 16.3 nM) and U-46619 (EC50 = 538.3 nM) potently stimulated aggregation (TP-receptor mediated effect), whereas AGN192093 was a much weaker agonist (EC50 = 37.9 microM). AGN192093 was not a partial agonist in platelets, since it did not antagonize aggregation induced by AGN191976, U-46619, arachidonic acid or ADP. These results provide evidence for a subdivision of TP-receptors, and AGN192093 appears to be able to distinguish between TP-receptors in smooth muscle and platelets. In the Beagle dog eye, both AGN191976 and AGN192093 were highly potent and efficacious ocular hypotensives. Single 2.5 micrograms doses of drug decreased IOP by 11.4 (AGN191976) and 7.7 mm Hg (AGN192093) relative to the contralateral control eye. In contrast, U-46619 did not lower IOP. AGN191976, but not U-46619, increased outflow facility in these animals, which is consistent with their effects on IOP. Neither compound caused miosis which is FP-receptor mediated in the dog. These studies suggest the existence of heterogeneous populations of TP-receptors. AGN191976 and AGN192093, two novel TP-receptor agonists, appear to be useful tools for the pharmacological distinction of TP-receptor subtypes.
authors.affiliation: Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Krauss
authors.forename: D F
authors.initials: DF
authors.lastname: Woodward
authors.forename: R M
authors.initials: RM
authors.lastname: Burk
authors.forename: T S
authors.initials: TS
authors.lastname: Gac
authors.forename: L L
authors.initials: LL
authors.lastname: Gibson
authors.forename: C E
authors.initials: CE
authors.lastname: Protzman
authors.forename: F
authors.initials: F
authors.lastname: Abbass
authors.forename: K
authors.initials: K
authors.lastname: Marshall
authors.forename: J
authors.initials: J
authors.lastname: Senior
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D002415:Cats; D002645:Chickens; D003228:Conjunctiva / Q000098:blood supply; D004285:Dogs; D005123:Eye / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated; D006168:Guinea Pigs; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007429:Intraocular Pressure / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D015814:Ocular Hypotension / Q000139:chemically induced; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D011680:Pupil / Q000187:drug effects; D051381:Rats; D017482:Receptors, Thromboxane / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: C098222:AGN 191976; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548