L-733,060, A NOVEL TACHYKININ NK1 RECEPTOR ANTAGONIST - EFFECTS IN [CA2+](I) MOBILIZATION, CARDIOVASCULAR AND DURAL EXTRAVASATION ASSAYS

This study investigated the propel-ties of a novel piperidine ether-ba sed tachykinin NK1 receptor antagonist L-733,060, 3,5-bis(trifluoromet hyl)phenyl)methyloxy)-2-phenyl piperidine and its 2R,3R-enantiomer L-7 33,061 on [Ca2+](i) mobilisation in Chinese hamster ovary cells transf ected with human tachykinin NK1 receptors, compared to their effects i n rodent cardiovascular and neurogenic plasma extravasation assays. Us ing FURA-2-imaging techniques, L-733,060 inhibited substance P-induced [Ca2+](i) mobilisation with an estimated affinity of 0.8 nM whereas L -733,061 (30-300 nM) did not. No significant effects of L-733,060 were observed on mean arterial blood pressure or heart rate in conscious o r anaesthetised rats at doses of < 3000 mu g kg(-1) i.v. L-733,060 als o stereoselectively inhibited neurogenic plasma extravasation in rat d ura produced by electrical stimulation of trigeminal nerves with an ID 50 of 212 +/- 19 mu g kg(-1) i.v. Thus, L-733,060 is a novel antagonis t of human tachykinin NK1 receptors which stereoselectively inhibits n eurogenic plasma extravasation at doses that do not cause adverse card iovascular effects.