Nonpeptide Tachykinin Receptor Antagonists. III. SB 235375, a Low Central Nervous System-Penetrant, Potent and Selective Neurokinin-3 Receptor Antagonist, Inhibits Citric Acid-Induced Cough and Airways Hyper-reactivity in Guinea Pigs

In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of (−)-( S )- N -(α-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide (SB 235375), a low central nervous system (CNS)-penetrant, human neurokinin-3 (NK-3) receptor (hNK-3R) antagonist, is described. SB 235375 inhibited 125I-[MePhe7]-neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with a K i = 2.2 nM and antagonized competitively NKB-induced Ca2+ mobilization in human embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a K b = 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA2 = 8.1) and guinea pig ileal circular smooth muscles (pA2 = 8.3). SB 235375 was selective for the hNK-3R compared with hNK-1 ( K i > 100,000 nM) and hNK-2 receptors ( K i = 209 nM), and was without effect, at 1 μM, in 68 other receptor, enzyme, and ion channel assays. Intravenous SB 235375 produced a dose-related inhibition of miosis induced by i.v. senktide in the rabbit (ED50 of 0.56 mg/kg). Intraperitoneal SB 235375 (10–30 mg/kg) inhibited citric acid-induced cough and airways hyper-reactivity in guinea pigs. In mice oral SB 235375 (3–30 mg/kg) was without significant effect on the behavioral responses induced by intracerebral ventricular administration of senktide. Pharmacokinetic evaluation in the mouse and rat revealed that oral SB 235375 was well absorbed systemically but did not effectively cross the blood-brain barrier. The preclinical profile of SB 235375, encompassing high affinity, selectivity, oral activity, and low CNS penetration, suggests that it is an appropriate tool compound to define the pathophysiological roles of the NK-3Rs in the peripheral nervous system. * NKA : neurokinin A NKB : neurokinin B CNS : central nervous system NK-1R : neurokinin-1 receptor NK-2R : neurokinin-2 receptor NK-3 : neurokinin-3 NK-3R : neurokinin-3 receptor PEG : polyethylene glycol CHO : Chinese hamster ovary CHO-hNK-3R : CHO cells stably expressing the human NK-3R CHO-hNK-2R : CHO cells stably expressing the human NK-2R CHO-hNK-1R : CHO cells expressing the human NK-1R HEK : human embryonic kidney HEK 293-hNK-3R : HEK 293 cells stably expressing the human NK-3R HEK 293-mNK-3R : HEK 293 cells transiently expressing the murine NK-3R HEK 293-mNK-2R : HEK 293 cells transiently expressing the murine NK-2R IC50 : concentration of antagonist causing 50% inhibition of agonist response K i : apparent inhibition constant K b : dissociation constant ANOVA : analysis of variance 5-HT : serotonin (5-hydroxytryptamine)