摘要：The pharmacological properties of the novel neurokinin-1 (NK1) receptor antagonist FK886, ([3,5-bis(trifluoromethyl)phenyl][(2 R )-2-(3-hydroxy-4-methylbenzyl)-4-{2-[(2 S )-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1-yl]methanone dihydrochloride), were studied. FK886 potently inhibited the binding of [125I]Bolton-Hunter-labeled substance P ([125I]BH-SP; 100 pM) to human NK1 receptors expressed in Chinese hamster ovary (CHO) cells (IC50=0.70 nM). It also possessed high affinities for dog, ferret, gerbil and guinea pig NK1 receptors, but not for rat NK1 receptor. FK886 was highly selective for the NK1 receptor, with 250- and >20000-fold selectivity for human NK1 over NK2 and NK3, 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 NK1 receptor-expressing CHO cells (IC50=1.4 nM) without stimulating NK1 receptors. The antagonism exerted by FK886 against human NK1 receptor was insurmountable in saturation binding experiments, with both the affinity and B max of [125I]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 NK1 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 NK1 receptor, and suggest that FK886 antagonizes various NK1 receptor-mediated biological effects in the central nervous system.
