title: Effects on the isolated human bronchus of SR 48968, a potent and selective nonpeptide antagonist of the neurokinin A (NK2) receptors.
abstract: Tachykinins produce concentration-dependent contraction of the human isolated bronchus by stimulation of receptors that belong to the NK2 type. The aim of this study was to investigate the inhibitory effects of a new, potent, and selective nonpeptide antagonist of the neurokinin A (NKA) (NK2) receptors, SR 48968 [(S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl) butyl]benzamide] on human isolated airways. Our experiments were performed on human isolated bronchi obtained from patients with lung cancer. Phosphoramidon, 10(-5) M, was added to the bath to inhibit neurokinin metabolism. SR 48968 induced a parallel shift to the right of the concentration-response (C/R) curves to [Nle10]-NKA(4-10), a specific NK2 receptor agonist. The antagonism was of the competitive type, with a pA2 of 9.40 +/- 0.19 (slope = 0.95 +/- 0.08, n = 13). The (R)-enantiomer of SR 48968 was 100-fold less potent and a noncompetitive antagonist (slope = 0.56 +/- 0.11, n = 8); pA2 and slope of the racemate were 8.86 +/- 0.21 and 1.09 +/- 0.21 (n = 7), respectively. Under similar conditions, racemic CP-96,345, a nonpeptide NK1 antagonist, did not modify the C/R curves to [Nle10]-NKA(4-10) until 10(-7) M. SR 48968 did not modify C/R curves to acetylcholine, histamine, KCI, or PGF2 alpha on the human isolated bronchus. Finally, SR 48968 shifted to the right C/R curves to substance P on isolated human bronchi, whereas racemic CP-96,345 was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Faculty of Medicine Paris-Ouest, France.
authors.forename: C
authors.initials: C
authors.lastname: Advenier
authors.forename: E
authors.initials: E
authors.lastname: Naline
authors.forename: L
authors.initials: L
authors.lastname: Toty
authors.forename: H
authors.initials: H
authors.lastname: Bakdach
authors.forename: X
authors.initials: X
authors.lastname: Emonds-Alt
authors.forename: P
authors.initials: P
authors.lastname: Vilain
authors.forename: J C
authors.initials: JC
authors.lastname: Brelière
authors.forename: G
authors.initials: G
authors.lastname: Le Fur
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects*; D016084:Bronchoconstriction / Q000187:drug effects; D006224:Cricetinae; D015237:Dinoprost / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004353:Drug Evaluation, Preclinical; D005260:Female; D006632:Histamine / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015288:Neurokinin A / Q000037:antagonists & inhibitors* / Q000187:drug effects; D010446:Peptide Fragments / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011189:Potassium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D019998:Racemases and Epimerases; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000145:classification / Q000187:drug effects*
chemical_list: D001549:Benzamides; D001713:Biphenyl Compounds; D010446:Peptide Fragments; D010880:Piperidines; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D011189:Potassium Chloride; C073839:SR 48968; D006632:Histamine; D015288:Neurokinin A; C056408:neurokinin A(4-10); D015237:Dinoprost; D019998:Racemases and Epimerases; D000109:Acetylcholine; C066892:CP 96345