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

Abstract

In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of (Ϫ)-(S)-N-(␣-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 125 I- [MePhe 7 ]-neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with a K i ϭ 2.2 nM and antagonized competitively NKB-induced Ca 2ϩ mobilization in human embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a K b ϭ 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA 2 ϭ 8.1) and guinea pig ileal circular smooth muscles (pA 2 ϭ 8.3). SB 235375 was selective for the hNK-3R compared with hNK-1 (K i Ͼ 100,000 nM) and hNK-2 receptors (K i ϭ 209 nM), and was without effect, at 1 M, 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 (ED 50 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.

A Potent and Selective Nonpeptide Antagonist of CXCR2 Inhibits Acute and Chronic Models of Arthritis in the Rabbit

“…42). The selectivity of the compound for human CXCR2 is further supported by its failure to compete for ligand-binding to other human chemokine receptors, including CXCR3, CXCR4, CCR2, CCR7, CCR8, and CX3CR1, as well as its lack of activity in 66 additional receptor binding and enzyme assays previously described (43).…”

Role of Neurokinin 3 Receptors in Supraoptic Vasopressin and Oxytocin Neurons

“…On the other hand, these negative results do not provide conclusive evidence that SP is not an effective endogenous ligand for the NK3-Rs in SON. Because the NK3 antagonists used have a lower affinity for rat NK3-Rs than for human NK3-Rs (Sarau et al, 2000;Hay et al, 2002), it is possible that the 100-fold excess of antagonist was not sufficient to block SP activation of NK3-Rs in the perifusion experiments. Furthermore, because SP has a lower affinity for NK3-Rs than senktide, it is possible that the concentration of SP injected was not sufficient to activate the NK3-Rs.…”

“…Subsequently, explants were perifused with basal medium or the indicated concentrations of SP (AnaSpec, San Jose, CA) or senktide (Tocris Cookson, Ellisville, MO). Explants were exposed to an NK1 antagonist, N-acetyl-L-tryptophan 3,5-bis(tri-fluoromethyl) benzyl ester (L732,138) (Sigma) (Cascieri et al, 1994) or one of two NK3-R antagonists, SB222200 and SB235375 (Sarau et al, 2000;Hay et al, 2002) (generously provided by GlaxoSmithKline, Research Triangle Park, NC), 30 min before the addition of SP. Drugs and peptides were dissolved directly into the medium with the exception of SB222200, which was dissolved in dimethylsulfoxide (DMSO).…”

The diagnosis and management of chronic cough

“…NK-receptor antagonists, such as the NK 2 -receptor antagonist, SR 48968, inhibit citric acidinduced cough in conscious guinea pigs [113], possibly via both a central and/or peripheral mechanism of action [114]. The NK 3 -receptor competitive antagonist, SB 235375, is also effective against citric acid-induced cough and an NK 1 /NK 2 / NK 3 -receptor antagonist, SCH 206272, inhibits capsaicininduced cough in the guinea-pig [115]. However, an NK 1 -receptor antagonist had no antitussive action in man [116].…”