Nonpeptide tachykinin receptor antagonists. II. Ppharmacological and pharmacokinetic profile of SB-222200, a central nervous system penetrant, potentand selective NK-3 receptor antagonist

The pharmacological and pharmacokinetic profile of SB-222200 [(S)-(-)-N-(al pha-ethylbenzyl)-3-methyl-2-phenylquinoline-4-carboxamide], a human NK-3 re ceptor (hNK-3R) antagonist, was determined. SB-222200 inhibited I-125-[MePh e(7)]neurokinin B (NKB) binding to Chinese hamster ovary (CHO) cell membran es stably expressing the hNK-3 receptor (CHO-hNK-3R) with a K-i = 4.4 nM an d antagonized NKB-induced Ca2+ mobilization in HEK 293 cells stably express ing the hNK-3 receptor (HEK 293-hNK-3R) with an IC50 = 18.4 nM. SB-222200 w as selective for hNK-3 receptors compared with hNK-1 (K-i > 100,000 nM) and hNK-2 receptors (K-i = 250 nM). In HEK 293 cells transiently expressing mu rine NK-3 receptors (HEK 293-mNK-3R), SB-222200 inhibited binding of I-125- [MePhe(7)]NKB (K-i = 174 nM) and antagonized NKB (1 nM)-induced calcium mob ilization (IC50 = 265 nM). In mice oral administration of SB-222200 produce d dose-dependent inhibition of behavioral responses induced by i.p. or intr acerebral ventricular administration of the NK-3 receptor-selective agonist , senktide, with ED50 values of approximately 5 mg/kg. SB-222200 effectivel y crossed the blood-brain barrier in the mouse and rat. The inhibitory effe ct of SB-222200 against senktide-induced behavioral responses in the mouse correlated significantly with brain, but not plasma, concentrations of the compound. Pharmacokinetic evaluation of SB-222200 in rat after oral adminis tration (8 mg/kg) indicated sustained plasma concentrations (C-max = about 400 ng/ml) and bioavailability of 46%. The preclinical profile of SB-222200 , demonstrating high affinity, selectivity, reversibility, oral activity, a nd central nervous system penetration, suggests that it will be a useful to ol compound to define the physiological and pathophysiological roles of NK- 3 receptors, in particular in the central nervous system.