title: Pharmacological properties of FK886, a new, centrally active neurokinin-1 receptor antagonist.
abstract: The pharmacological properties of the novel neurokinin-1 (NK(1)) receptor antagonist FK886, ([3,5-bis(trifluoromethyl)phenyl][(2R)-2-(3-hydroxy-4-methylbenzyl)-4-{2-[(2S)-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1-yl]methanone dihydrochloride), were studied. FK886 potently inhibited the binding of [(125)I]Bolton-Hunter-labeled substance P ([(125)I]BH-SP; 100 pM) to human NK(1) receptors expressed in Chinese hamster ovary (CHO) cells (IC(50)=0.70 nM). It also possessed high affinities for dog, ferret, gerbil and guinea pig NK(1) receptors, but not for rat NK(1) receptor. FK886 was highly selective for the NK(1) receptor, with 250- and >20000-fold selectivity for human NK(1) over NK(2) and NK(3), respectively. Further, it did not inhibit radioligand binding at 54 different sites, including receptors, ion channels and transporters. FK886 inhibited substance P (3.2 nM)-induced inositol phosphate formation in human NK(1) receptor-expressing CHO cells (IC(50)=1.4 nM) without stimulating NK(1) receptors. The antagonism exerted by FK886 against human NK(1) receptor was insurmountable in saturation binding experiments, with both the affinity and B(max) of [(125)I]BH-SP being significantly reduced. After intravenous administration, FK886 (0.01-0.1 mg/kg) dose-dependently inhibited the foot-tapping behavior induced by intracerebroventricular administration of a selective NK(1) receptor agonist, GR73632 (10 pmol), in gerbils, with significant inhibition being observed at doses of 0.032-0.1 mg/kg, indicating excellent brain penetration. The brain penetration of FK886 was further demonstrated by the cerebral distribution of radioactivity after intravenous injection of radiolabeled FK886. Taken together, these results demonstrate that FK886 is a potent, highly selective and centrally active, insurmountable antagonist of the NK(1) receptor, and suggest that FK886 antagonizes various NK(1) receptor-mediated biological effects in the central nervous system.
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305–8585, Japan. takako.furukawa@astellas.com
authors.forename: Takako
authors.initials: T
authors.lastname: Yoshino-Furukawa
authors.forename: Yasue
authors.initials: Y
authors.lastname: Maeda
authors.forename: Aya
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakuma
authors.forename: Katsunori
authors.initials: K
authors.lastname: Imazumi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamakuni
authors.forename: Hajime
authors.initials: H
authors.lastname: Sogabe
authors.forename: Masahiko
authors.initials: M
authors.lastname: Matsuo
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Manda
authors.forename: Wataru
authors.initials: W
authors.lastname: Uchida
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005849:Gerbillinae; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: C581895:FK886; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010879:Piperazines; D018040:Receptors, Neurokinin-1; D011994:Recombinant Proteins; C068032:GR 73632; D013373:Substance P