Bimatoprost (Lumigan((R))) is an agonist at the cloned human ocular FP prostaglandin receptor: real-time FLIPR-based intracellular Ca(2+) mobilization studies.
Bimatoprost is the ethyl amide derivative of 17-phenyl-trinor prostaglandin F(2alpha). Here, we show that bimatoprost (K(i)=9250+/-846nM) and bimatoprost free acid (17-phenyl-trinor prostaglandin F(2alpha); K(i)=59+/-6nM) bind to the FP receptor and displace [(3)H]-travoprost acid, a selective FP agonist. Bimatoprost (EC(50)=3070+/-1330nM), Lumigan((R)) (bimatoprost 0.03% ophthalmic solution; EC(50)=1150+/-93nM) and bimatoprost acid (EC(50)=15+/-3nM) mobilized intracellular Ca(2+) ([Ca(2+)](i)) in <5s in HEK-293 cells expressing the cloned human ciliary body FP receptor on a fluorometric imaging plate reader (FLIPR). Furthermore, agonist effects of bimatoprost and bimatoprost acid were blocked by AL-8810 (11beta-fluoro-15-epi-15-indanyl prostaglandin F(2alpha); K(i)=0.7-2.1 MicroM), an FP receptor-selective antagonist. Therefore, the prodrug bimatoprost and its hydrolytic product, bimatoprost free acid, bind to and activate the human ocular FP prostaglandin receptor to mobilize [Ca(2+)](i), thus behaving as FP receptor agonists.
Sharif
N A
NA
Molecular Pharmacology Unit (R2-19), Alcon Research Limited, 6201 South Freeway, 76134, Fort Worth, TX, USA. naj.sharif@alconlabs.com
Kelly
C R
CR
Williams
G W
GW
D000577:Amides; D000069580:Bimatoprost; D002118:Calcium / Q000378:metabolism*; D002924:Ciliary Body / Q000378:metabolism*; D003001:Cloning, Molecular; D003008:Cloprostenol / Q000819:agonists / Q000031:analogs & derivatives* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005123:Eye / Q000378:metabolism; D005470:Fluorometry; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000069557:Travoprost
D000577:Amides; D008055:Lipids; D011982:Receptors, Prostaglandin; D011993:Recombinant Fusion Proteins; D003008:Cloprostenol; D000069580:Bimatoprost; D002118:Calcium; D000069557:Travoprost