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
| Autor: | Douglas W. P. Hay, Raveglia Luca Francesco, Don E. Griswold, Brian Bush, Punam Sandhu, Henry M. Sarau, Dulcie B. Schmidt, Giuseppe Giardina, James J. Foley, Mario Grugni, Jeffrey J. Legos, Lenox D. Martin, Dave Lundberg, Charles J. Kotzer, David J. Kilian, William Potts, Frank C. Barone, Mark A. Luttmann, David C. Underwood |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Central Nervous System
Male Neurokinin A Guinea Pigs Iris Acetates In Vitro Techniques Substance P Biology Pharmacology Citric Acid Guinea pig Mice Radioligand Assay In vivo medicine Animals Cloning Molecular Receptor Receptors Tachykinin Mice Inbred BALB C Behavior Animal Chinese hamster ovary cell HEK 293 cells Antagonist Muscle Smooth Pupil Receptors Neurokinin-3 Peptide Fragments Recombinant Proteins Rats Antitussive Agents medicine.anatomical_structure Cough Peripheral nervous system Quinolines Molecular Medicine Calcium Rabbits Bronchial Hyperreactivity Tachykinin receptor Muscle Contraction |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 300:314-323 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | In this report the in vitro and in vivo pharmacological and 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 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 Ca(2+) 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 (pA(2) = 8.1) and guinea pig ileal circular smooth muscles (pA(2) = 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 microM, 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|