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

• DOI: 10.1124/jpet.300.1.314
• Publication Date: 2003-01-10T18:30:34Z
• Authors: Douglas W.P. Hay; Giuseppe A.M. Gia...; Don E. Griswold; David C. Underwood; Charles J. Kotzer; Brian Bush; William Potts; Punam Sandhu; Dave Lundberg; James J. Foley; Dulcie B. Schmidt; Lenox D. Martin; David Kilian; Jeffrey J. Legos; Frank C. Barone; Mark A. Luttmann; Mario Grugni; Luca F. Raveglia; Henry M. Sarau
• Keywords: Tachykinin receptor; Neurokinin B; Neurokinin A; Tachykinin receptor 1

In this report the in vitro and vivo pharmacological pharmacokinetic profile of (-)-(S)-N-(alpha-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 Chinese hamster ovary (CHO) cells expressing hNK-3R (CHO-hNK-3R) with K(i) = 2.2 nM antagonized competitively NKB-induced Ca(2+) mobilization embryonic kidney (HEK) 293 (HEK 293-hNK-3R) K(b) 12 nM. senktide (NK-3R)-induced contractions rabbit isolated iris sphincter (pA(2) 8.1) guinea pig ileal circular smooth muscles 8.3). was selective for compared hNK-1 (K(i) > 100,000 nM) hNK-2 receptors 209 nM), without effect, at 1 microM, 68 other receptor, enzyme, ion channel assays. Intravenous produced dose-related inhibition miosis induced by i.v. (ED(50) 0.56 mg/kg). Intraperitoneal (10-30 mg/kg) citric acid-induced cough airways hyper-reactivity pigs. mice oral (3-30 significant effect on behavioral responses intracerebral ventricular administration senktide. Pharmacokinetic evaluation mouse rat revealed that well absorbed systemically but did not effectively cross blood-brain barrier. The preclinical 235375, encompassing high affinity, selectivity, activity, CNS penetration, suggests it an appropriate tool compound define pathophysiological roles NK-3Rs peripheral system.