AGN 191976: a novel thromboxane A2-mimetic with ocular hypotensive properties.
The possible subdivision of thromboxane A2-sensitive (TP) receptors is currently a controversial subject. We report herein on a novel thromboxane A2 mimetic, AGN 191976, which has almost identical pharmacological activity to the well-characterized prostaglandin H2/thromboxane A2 (PGH2/TxA2) mimetic U-46619, but its effects on intraocular pressure are quite distinct from U-46619. Prostanoid receptor activity was determined in vitro using different smooth muscle assays and platelets. Intraocular pressure was measured tonometrically in ocular normotensive Beagle dogs and Cynomolgus monkeys. Conjunctival microvascular permeability was determined in guinea pigs. Despite closely resembling U-46619 as a potent and selective TP receptor agonist, AGN 191976 was a potent ocular hypotensive in dogs and monkeys whereas U-46619 did not lower IOP in either species. The ocular hypotensive effect of AGN 191976 in dogs was attenuated by pretreatment with the TP receptor antagonist SQ 29548. Thus, the ocular hypotensive effects of AGN 191976 are consistent with TP receptor stimulation. Both TxA2-mimetics caused plasma leakage in the guinea pig conjunctiva. The disparate activities of U-46619 and AGN 191976 in our studies suggest the existence of heterogeneous populations of TP-receptors in the eye.
Krauss
A H
AH
Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.
Woodward
D F
DF
Chen
J
J
Gibson
L L
LL
Lai
R K
RK
Protzman
C E
CE
Shan
T
T
Williams
L S
LS
Gac
T S
TS
Burk
R M
RM
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000368:Aged; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D003228:Conjunctiva / Q000098:blood supply; D004285:Dogs; D005231:Fatty Acids, Unsaturated; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007429:Intraocular Pressure / Q000187:drug effects*; D008252:Macaca fascicularis; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009798:Ocular Hypertension / Q000139:chemically induced*; D009883:Ophthalmic Solutions; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011680:Pupil / Q000187:drug effects; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D014065:Tonometry, Ocular; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C098222:AGN 191976; D000959:Antihypertensive Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D009883:Ophthalmic Solutions; 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