PHARMACOLOGICAL CHARACTERIZATION of NOVEL NON-PEPTIDE NEUROKININ-A (NKA) ANTAGONISTS that DEMONSTRATE SPECIES SELECTIVITY

We examined the pharmacology of ZM253,270 (4-1 (4-chlorophenyl) amino)-5,6-dihydro-2-[4-(2-(hydroxyimino)l-oxopropyl]-l-piperazyinyl]-6(1- methylethyl) TH-pyrrolo [3,4-d]pyrimidin-7-one and two representative examples of the pyrrolopyrimidines, a novel class of non-peptide, NK-2 receptor (NK-2R) antagonists. ZM253.270 competitively inhibited [³H]NKA binding to native or cloned NK-2R from hamster urinary bladder (Ki = 2 nM). but was a weaker (48 fold) inhibitor of [³H]NKA binding to cloned human NK-2R. A similar species selectivity was observed with weaker analogs of ZM253.270. The pyrrolopyrimidines demonstrated only marginal inhibition of [³H]SP binding to NK-1R in cloned human or guinea-pig lung membranes NK-1R (Ki > 2 μM). In hamster trachea, ZM253.27Ü competitively antagonized the contractile response evoked by neurokinin A (NKA, -logK_B = 7.5). In human bronchus, ZM253.270 was about 90 fold less potent as a competitive antagonist of NKA. The data from ligand and functional receptor assays in airway smooth muscles, demonstrate that the novel non-peptide antagonist ZM253,270 is selective for the NK2R species prevalent in hamster, compared with those found in human tissues. A162 PHARMACOLOGICAL CHARACTERIZATION OF NOVEL NON-PEPTIDE NEUROKININ-A (NKA) ANTAGONISTS THAT DEMONSTRATE SPECIES SELECTIVITY D. Aharony. C.K. Buckner. J.L. Ellis. S.V. Ghanekar. A. Graham. J.S. Kays. J. Little. S. Meeker. S.C. Miller. B.J. Undem and I.R. Waldron ZENECA Pharmaceuticals, Wilmington, DE 19897, and Center for Asthma and Allergy, John Hopkins University, Baltimore MD. We examined the pharmacology of ZM253,270 (4-1 (4-chlorophenyl) amino)-5,6-dihydro-2-[4-(2-(hydroxyimino)l-oxopropyl]-l-piperazyinyl]-6(1- methylethyl) TH-pyrrolo [3,4-d]pyrimidin-7-one and two representative examples of the pyrrolopyrimidines, a novel class of non-peptide, NK-2 receptor (NK-2R) antagonists. ZM253.270 competitively inhibited [³H]NKA binding to native or cloned NK-2R from hamster urinary bladder (Ki = 2 nM). but was a weaker (48 fold) inhibitor of [³H]NKA binding to cloned human NK-2R. A similar species selectivity was observed with weaker analogs of ZM253.270. The pyrrolopyrimidines demonstrated only marginal inhibition of [³H]SP binding to NK-1R in cloned human or guinea-pig lung membranes NK-1R (Ki > 2 μM). In hamster trachea, ZM253.27Ü competitively antagonized the contractile response evoked by neurokinin A (NKA, -logK_B = 7.5). In human bronchus, ZM253.270 was about 90 fold less potent as a competitive antagonist of NKA. The data from ligand and functional receptor assays in airway smooth muscles, demonstrate that the novel non-peptide antagonist ZM253,270 is selective for the NK2R species prevalent in hamster, compared with those found in human tissues.