Effects on the isolated human bronchus of SR 48968, a potent and selective nonpeptide antagonist of the neurokinin A (NK2) receptors

• Published in: The American review of respiratory disease Vol. 146; no. 5 Pt 1; p. 1177
• Main Authors: Advenier, C, Naline, E, Toty, L, Bakdach, H, Emonds-Alt, X, Vilain, P, Brelière, J C, Le Fur, G
• Format: Journal Article
• Language: English
• Published: United States 01-11-1992
• Subjects: Acetylcholine - administration & dosage; Acetylcholine - pharmacology; Amino Acid Sequence; Animals; Benzamides - administration & dosage; Benzamides - chemistry; Benzamides - pharmacology; Biphenyl Compounds - pharmacology; Bronchi - drug effects; Bronchoconstriction - drug effects; Cricetinae; Dinoprost - administration & dosage; Dinoprost - pharmacology; Dose-Response Relationship, Drug; Drug Antagonism; Drug Evaluation, Preclinical; Female; Histamine - administration & dosage; Histamine - pharmacology; Humans; In Vitro Techniques; Male; Middle Aged; Molecular Sequence Data; Neurokinin A - antagonists & inhibitors; Neurokinin A - drug effects; Peptide Fragments - drug effects; Piperidines - administration & dosage; Piperidines - chemistry; Piperidines - pharmacology; Potassium Chloride - administration & dosage; Potassium Chloride - pharmacology; Racemases and Epimerases; Receptors, Neurokinin-2; Receptors, Neurotransmitter - classification; Receptors, Neurotransmitter - drug effects
• ISSN: 0003-0805
• DOI: 10.1164/ajrccm/146.5_Pt_1.1177

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.