title: Nonpeptide tachykinin receptor antagonists. II. Pharmacological and pharmacokinetic profile of SB-222200, a central nervous system penetrant, potent and selective NK-3 receptor antagonist.
abstract: The pharmacological and pharmacokinetic profile of SB-222200 [(S)-(-)-N-(alpha-ethylbenzyl)-3-methyl-2-phenylquinoline-4-car boxami de], 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.
authors.affiliation: The Departments of Pulmonary Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Sarau
authors.forename: D E
authors.initials: DE
authors.lastname: Griswold
authors.forename: B
authors.initials: B
authors.lastname: Bush
authors.forename: W
authors.initials: W
authors.lastname: Potts
authors.forename: P
authors.initials: P
authors.lastname: Sandhu
authors.forename: D
authors.initials: D
authors.lastname: Lundberg
authors.forename: J J
authors.initials: JJ
authors.lastname: Foley
authors.forename: D B
authors.initials: DB
authors.lastname: Schmidt
authors.forename: E F
authors.initials: EF
authors.lastname: Webb
authors.forename: L D
authors.initials: LD
authors.lastname: Martin
authors.forename: J J
authors.initials: JJ
authors.lastname: Legos
authors.forename: R G
authors.initials: RG
authors.lastname: Whitmore
authors.forename: F C
authors.initials: FC
authors.lastname: Barone
authors.forename: A D
authors.initials: AD
authors.lastname: Medhurst
authors.forename: M A
authors.initials: MA
authors.lastname: Luttmann
authors.forename: G A
authors.initials: GA
authors.lastname: Giardina
authors.forename: D W
authors.initials: DW
authors.lastname: Hay
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007498:Iris / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000494:pharmacology; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; D011804:Quinolines; D018042:Receptors, Neurokinin-3; C109112:SB 222200; C054724:senktide; D013373:Substance P; D002118:Calcium