7,7-Difluoroprostacyclin derivative, AFP-07, a highly selective and potent agonist for the prostacyclin receptor.
Recently, we cloned cDNAs for the prostacyclin receptor (IP) and the four mouse PGE receptor subtypes, EP1, EP2, EP3, and EP4, and established Chinese hamster ovary cells that stably express each receptor. We examined the agonist potency and selectivity of AFP-07, a 7,7-difluoroprostacyclin derivative, compared with widely used stable prostacyclin analogue, iloprost, using the cells expressing each cloned receptor. AFP-07 strongly displaced the [3H] iloprost binding to the IP receptor-expressing cell membranes, the half maximal concentration for the displacement being 3 nM, which was one order lower than that of iloprost. AFP-07 concentration-dependently stimulated cAMP formation in the IP-expressing cells, the half-maximal concentration for the stimulation being 10 pM, which was one order lower than that of iloprost. On the other hand, AFP-07 showed lower affinity for EP1, EP2, EP3, and EP4 than PGE2, but iloprost had the same affinity as PGE2 for the EP1, These results demonstrate that AFP-07 is a potent and highly selective agonist for the IP receptor.
Chang
C S
CS
Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Japan. aichikaw@pharmsun.pharm.kyoto-u.ac.jp
Negishi
M
M
Nakano
T
T
Morizawa
Y
Y
Matsumura
Y
Y
Ichikawa
A
A
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D016285:Iloprost / Q000378:metabolism; D051379:Mice; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000819:agonists*; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype
C106189:AFP 03; C106190:AFP 06; C106191:AFP 07; C545636:Ptger1 protein, mouse; C545651:Ptger4 protein, mouse; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; C040805:7-fluoroprostacyclin; D011464:Epoprostenol; D000242:Cyclic AMP; D016285:Iloprost; D015232:Dinoprostone