Effect of non-peptide tachykinin NK1 receptor antagonists on non-adrenergic, non-cholinergic neurogenic mucus secretion in ferret trachea

We investigated, in ferret trachea in vitro, the binding characteristics an d the inhibition of non-adrenergic, non-cholinergic (NANC) neural mucus sec retion of four tachykinin receptor antagonists: the non-peptide tachykinin NK1 receptor antagonists CGP 49823 ((2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl )-4-(quinolin-mu-ylmethl amino) piperidine) and CGP 55000 ((2R,4S)-2-benzyl -1-(3,5-bistrifluoromethyl-benzoyl)-4-(quinolinyl-methylamino)piperidine) a nd CP 99,994 ((+)-(2S,3S)-3-methoxybenzyl amino)-2-phenylpiperidine), and t he peptide tachykinin NK2 receptor antagonist MEN 10,627 (cyclo(Met-Asp-Trp -Phe-Dap-Leu)cyclo(2 beta-5 beta)). CGP 49823, CGP 55000 and CP 99,994 conc entration-dependently displaced [I-125]Bolton-Hunter substance P binding in tracheal membranes with Hill coefficients not different from unity and IC5 0 values of 1.4, 1.7 and 1.3 nM, respectively. In contrast, MEN 10,627 disp laced binding according to a two-site model, with IC(50)s of 0.2 nM and 1.3 mu M. Electrical stimulation of tracheal segments with adrenoceptor and ch olinoceptor blockade increased output of the mucus marker (SO4)-S-35 by 59% above baseline (representing the NANC neural secretory response). CGP 4982 3, CGP 55000 or CP 99,994 concentration-dependently inhibited NANC neural s ecretion with IC50 values of 30, 8 and 120 nM, respectively. In contrast, M EN 10,627 (3 mu M) did not inhibit secretion. The NK1 antagonists, but not the NK2 antagonist, inhibited [Sar(9)]substance P-induced secretion, while none of the antagonists affected acetylcholine-induced secretion. We conclu de that NANC neural secretion in ferret trachea in vitro is a useful test s ystem for tachykinin NK1 receptor antagonists with therapeutic potential in conditions of the airways in which tachykininergic mechanisms and mucus hy persecretion are implicated in pathophysiology, for example asthma and chro nic bronchitis. (C) 1999 Elsevier Science B.V. All rights reserved.