Nonpeptide Tachykinin Receptor Antagonists. II. Pharmacological and Pharmacokinetic Profile of SB-222200, a Central Nervous System Penetrant, Potent and Selective NK-3 Receptor Antagonist

The pharmacological and pharmacokinetic profile of SB-222200 [( S )-(−)- N -(α-ethylbenzyl)-3-methyl-2-phenylquinoline-4-carboxamide], a human NK-3 receptor (hNK-3R) antagonist, was determined. SB-222200 inhibited 125 I-[MePhe 7 ]neurokinin B (NKB) binding to Chinese hamster ovary (CHO) cell membranes stably expressing the hNK-3 receptor (CHO-hNK-3R) with a K i = 4.4 nM and antagonized NKB-induced Ca 2+ mobilization in HEK 293 cells stably expressing the hNK-3 receptor (HEK 293-hNK-3R) with an IC 50 = 18.4 nM. SB-222200 was 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 murine NK-3 receptors (HEK 293-mNK-3R), SB-222200 inhibited binding of 125 I-[MePhe 7 ]NKB ( K i = 174 nM) and antagonized NKB (1 nM)-induced calcium mobilization (IC 50 = 265 nM). In mice oral administration of SB-222200 produced dose-dependent inhibition of behavioral responses induced by i.p. or intracerebral ventricular administration of the NK-3 receptor-selective agonist, senktide, with ED 50 values of approximately 5 mg/kg. SB-222200 effectively crossed the blood-brain barrier in the mouse and rat. The inhibitory effect 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 administration (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, and central nervous system penetration, suggests that it will be a useful tool compound to define the physiological and pathophysiological roles of NK-3 receptors, in particular in the central nervous system.