Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP receptor agonist, as an ocular hypotensive drug.

To evaluate the pharmacological characteristics of AFP-168 (tafluprost), a new prostaglandin (PG) F(2alpha) derivative, we examined its receptor-binding affinities, intraocular pressure (IOP)-lowering effect, effects on aqueous humor dynamics, and stimulating effect on melanogenesis. The receptor-binding profile for AFP-172, a carboxylic acid of AFP-168, was determined by measuring muscle contractions in an organ bath, inhibition of platelet aggregation, and competitive binding of a radio-labelled ligand. For the IOP-measurement study, ocular normotensive and laser-induced ocular hypertensive cynomolgus monkeys were used, and IOP was measured using a pneumatonograph. For the studies of aqueous humor dynamics, IOP (Goldmann applanation tonometry), fluorophotometry, two-level constant pressure perfusion, and isotope dilution and accumulation techniques were used in ocular normotensive monkeys. The melanin contents in the medium and in the cell bodies of cultured B16-F0 melanoma cells were measured. The affinity for the FP receptor shown by AFP-172 (Ki : 0.4 nm) was 12 times that of PhXA85 ( Ki : 4.7 nm), a carboxylic acid of latanoprost. A single application of AFP-168 at 0.0025% significantly lowered IOP in both ocular normotensive and hypertensive monkeys (3.1 and 11.8 mmHg, respectively, p < 0.01) and latanoprost at 0.005% significantly lowered IOP (2.1 mmHg, p < 0.01 and 9.5 mmHg, p = 0.059 respectively). Once daily instillation of AFP-168 at 0.001, 0.0025, or 0.005% for 5 days in normotensive monkeys significantly reduced IOP not only for a few hours, but also at the drug-trough time 24hr after application. Latanoprost at 0.005% also reduced IOP, but not at the drug-trough time. AFP-168 decreased IOP mainly by increasing uveoscleral outflow by 65% (p < 0.05) and, as sometimes seen with other prostanoids, also increased total outflow facility (33% increase, p < 0.05). In cultured B16-F0 melanoma cells, AFP-172 (100 microM) did not stimulate melanogenesis, but PhXA85 (100 microM) did. These findings indicate that AFP-168 has a high affinity for the prostanoid FP receptor, has potent IOP-lowering effects in both ocular normotensive and hypertensive monkeys that exceed those of latanoprost, and has less stimulating effect on melanogenesis in melanoma cells.
AuthorsYasutaka Takagi, Tadashi Nakajima, Atsushi Shimazaki, Masaaki Kageyama, Takeshi Matsugi, Yasushi Matsumura, B'Ann T Gabelt, Paul L Kaufman, Hideaki Hara
JournalExperimental eye research (Exp Eye Res) Vol. 78 Issue 4 Pg. 767-76 (Apr 2004) ISSN: 0014-4835 [Print] England
PMID15037111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • (5Z)-7-((1R,2R, 3R,5S)-2-((1E)-3,3-difluoro-4-phenoxy -1-butenyl)-3,5-dihydroxycyclopentyl)-5-heptenoic acid
  • Antihypertensive Agents
  • Prostaglandins F
  • Prostaglandins F, Synthetic
  • Receptors, Prostaglandin
  • prostaglandin F2alpha receptor
  • tafluprost
  • Latanoprost
  • Animals
  • Antihypertensive Agents (pharmacology)
  • Aqueous Humor (drug effects)
  • Binding, Competitive
  • Cell Line, Tumor
  • Eye Color (drug effects)
  • Glaucoma (drug therapy)
  • Guinea Pigs
  • Intraocular Pressure (drug effects)
  • Latanoprost
  • Macaca fascicularis
  • Male
  • Melanosis
  • Prostaglandins F (pharmacology)
  • Prostaglandins F, Synthetic (pharmacology)
  • Protein Binding
  • Receptors, Prostaglandin (metabolism)

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