title: Pharmacological characterization of SR 142801: a new non-peptide antagonist of the neurokinin NK-3 receptor.
abstract: Pharmacological and biochemical assays were performed to characterize SR 142801, a new NK-3 receptor antagonist, and its [R]-enantiomer, SR 142806. The compounds were tested (1) in the guinea pig isolated ileum stimulated with [MePhe7]NKB (NK-3 system) in order to evaluate onset and duration of action and to estimate the apparent affinity of the antagonist in terms of pA2 at 140 min after application; (2) in 6 selected monoreceptor systems, the rabbit (rb) vena cava for the NK-1rb receptor, the rabbit pulmonary artery and the hamster (hs) urinary bladder for the NK-2rb and NK-2hs receptors, the rat (r) portal vein for the NK-3r receptor, and in two multireceptor systems adequately treated with NK-1 or NK-2 receptor antagonists to obtain monoreceptor-mediated biological responses (the rat urinary bladder treated with SR 48968 for evaluating the NK-1r and the guinea pig-gp-ileum treated with CP-99994 for measuring the antagonist affinity on the NK-3gp receptor), in order to evaluate the antagonist selectivity, and (3) in various plasma membrane preparations containing NK-3-binding sites from rats, guinea pigs, and man. The data presented indicate that SR 142801 is a potent, fairly selective non-peptide antagonist of the functional (pA2 9.4) and binding (Ki 0.11 nmol/l) site of the guinea pig and human (Ki 0.21 nmol/l) NK-3 receptors, while being much less active on the Nk-3 receptors of other species, particularly the rat (pA2 7.0; Ki 15 nmol/l). SR 142801 shows a slow onset of action and acts as a long-lasting irreversible antagonist, specific for neurokinin receptors, especially the NK-3 sites of guinea pigs and man.
authors.affiliation: Department of Pharmacology, Medical School, Université de Sherbrooke, Qué., Canada.
authors.forename: X K
authors.initials: XK
authors.lastname: Nguyen-Le
authors.forename: Q T
authors.initials: QT
authors.lastname: Nguyen
authors.forename: F
authors.initials: F
authors.lastname: Gobeil
authors.forename: L H
authors.initials: LH
authors.lastname: Pheng
authors.forename: X
authors.initials: X
authors.lastname: Emonds-Alt
authors.forename: J C
authors.initials: JC
authors.lastname: Brelière
authors.forename: D
authors.initials: D
authors.lastname: Regoli
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D008647:Mesocricetus; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*
chemical_list: D010880:Piperidines; D018042:Receptors, Neurokinin-3; C091554:SR 142801