TY - JOUR T1 - 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 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 314 LP - 323 DO - 10.1124/jpet.300.1.314 VL - 300 IS - 1 AU - Douglas W. P. Hay AU - Giuseppe A. M. Giardina AU - Don E. Griswold AU - David C. Underwood AU - Charles J. Kotzer AU - Brian Bush AU - William Potts AU - Punam Sandhu AU - Dave Lundberg AU - James J. Foley AU - Dulcie B. Schmidt AU - Lenox D. Martin AU - David Kilian AU - Jeffrey J. Legos AU - Frank C. Barone AU - Mark A. Luttmann AU - Mario Grugni AU - Luca F. Raveglia AU - Henry M. Sarau Y1 - 2002/01/01 UR - http://jpet.aspetjournals.org/content/300/1/314.abstract N2 - 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 aK 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. NKAneurokinin ANKBneurokinin BCNScentral nervous systemNK-1Rneurokinin-1 receptorNK-2Rneurokinin-2 receptorNK-3neurokinin-3NK-3Rneurokinin-3 receptorPEGpolyethylene glycolCHOChinese hamster ovaryCHO-hNK-3RCHO cells stably expressing the human NK-3RCHO-hNK-2RCHO cells stably expressing the human NK-2RCHO-hNK-1RCHO cells expressing the human NK-1RHEKhuman embryonic kidneyHEK 293-hNK-3RHEK 293 cells stably expressing the human NK-3RHEK 293-mNK-3RHEK 293 cells transiently expressing the murine NK-3RHEK 293-mNK-2RHEK 293 cells transiently expressing the murine NK-2RIC50concentration of antagonist causing 50% inhibition of agonist responseKiapparent inhibition constantKbdissociation constantANOVAanalysis of variance5-HTserotonin (5-hydroxytryptamine) ER -