title: Comparative, general pharmacology of SDZ NKT 343, a novel, selective NK1 receptor antagonist.
abstract: 1. The in vitro and in vivo pharmacology of SDZ NKT 343 (2-nitrophenyl-carbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N- methylamide), a novel tachykinin NK1 receptor antagonist was investigated. 2. SDZ NKT 343 inhibited [3H]-substance P binding to the human NK1 receptor in transfected Cos-7 cell membranes (IC50 = 0.62+/-0.11 nM). In comparison, in the same assay Ki values for FK888, CP 99,994, SR 140,333 and RPR 100,893 were 2.13+/-0.04 nM, 0.96+/-0.20 nM, 0.15+/-0.06 nM and 1.77+/-0.41 nM, respectively. SDZ NKT 343 showed a markedly lower affinity at rat NK1 receptors in whole forebrain membranes (IC50 = 451+/-139 nM). 3. SDZ NKT 343 caused an increase in EC50 as well as reduction in the number of binding sites (Bmax) determined for [3H]-substance P, suggesting a non-competitive interaction at the human NK1 receptor. SDZ NKT 343 also caused a reduction in the maximum elevation of [Ca2+]i evoked by substance P (SP) in human U373MG cells and depressed the maximum [Sar9]SP sulphone-induced contraction of the guinea-pig isolated ileum. The antagonism of SP effects on U373MG cells by SDZ NKT 343 was reversible. 4. SDZ NKT 343 showed weak affinity to human NK2 and NK3 receptors in transfected Cos-7 cells (Ki of 0.52+/-0.04 microM and 3.4+/-1.2 microM, respectively). SDZ NKT 343 was inactive in a broad array of binding assays including the bradykinin B2 receptor the histamine H1 receptor, opiate receptors and adrenoceptors. SDZ NKT 343 only weakly inhibited the voltage-activated Ca2+ and Na+ currents in guinea-pig dorsal root ganglion neurones. The enantiomer of SDZ NKT 343, (R,R)-SDZ NKT 343 was about 1000 times less active at human NK1 receptors expressed in Cos-7 cell membranes. 5. Contractions of the guinea-pig ileum by [Sar9]SP sulphone were inhibited by SDZ NKT 343 in a concentration-dependent manner, with an IC50 = 1.60+/-0.94 nM, while the enantiomer (R,R)-SDZ NKT 343 was 100 times less active (IC50 = 162+/-26 nM). In comparison, in the same assay IC50 values for other NK1 receptor antagonists CP 99,994, SR 140,333, RPR 100,893 and FK 888 were 2.90+/-07 nM, 0.14+/-0.02 nM, 11.4+/-2.9 nM and 2.4+/-0.83 nM, respectively. 6. In anaesthetized guinea-pigs i.v. administered SDZ NKT 343 antagonized [Sar9]SP sulphone-evoked bronchoconstriction (70% reduction at 0.4 mg kg(-1), i.v.). Basal airway resistance, mean arterial blood pressure and heart rate were not affected. 7. In conclusion, SDZ NKT 343 is a highly selective NK1 receptor antagonist with high potency at the human and guinea-pig receptors. SDZ NKT 343 may be used as a potential novel therapeutic agent in human diseases where NK1 receptor hyperfunction is involved.
authors.affiliation: Novartis Institute for Medical Sciences, London.
authors.forename: C S
authors.initials: CS
authors.lastname: Walpole
authors.forename: M C
authors.initials: MC
authors.lastname: Brown
authors.forename: I F
authors.initials: IF
authors.lastname: James
authors.forename: E A
authors.initials: EA
authors.lastname: Campbell
authors.forename: P
authors.initials: P
authors.lastname: McIntyre
authors.forename: R
authors.initials: R
authors.lastname: Docherty
authors.forename: S
authors.initials: S
authors.lastname: Ko
authors.forename: L
authors.initials: L
authors.lastname: Hedley
authors.forename: S
authors.initials: S
authors.lastname: Ewan
authors.forename: K H
authors.initials: KH
authors.lastname: Buchheit
authors.forename: L A
authors.initials: LA
authors.lastname: Urban
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D017931:DNA Primers; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D005849:Gerbillinae; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013373:Substance P / Q000378:metabolism
chemical_list: D017931:DNA Primers; D009281:Naphthalenes; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D011994:Recombinant Proteins; C113385:SDZ NKT 343; D013373:Substance P; D011392:Proline