PHARMACOLOGICAL CHARACTERIZATION OF A NEW CLASS OF NONPEPTIDE NEUROKININ A ANTAGONISTS THAT DEMONSTRATE SPECIES SELECTIVITY

We examined the pharmacology of ZM1253,270 and two representative exam ples of the pyrrolopyrimidines, a new class of nonpeptide, NK-2 recept or (NK-2R) antagonists. ZM253,270 competitively inhibited [H-3]NKA bin ding to native or cloned NK-2R from hamster urinary bladder (K-i = 2 n M), but was a weaker (48-fold) inhibitor of [H-3]NKA binding to cloned human NK-2R. A similar species selectivity was observed with less pot ent analogs of ZM253,270. The pyrrolopyrimidines demonstrated only mar ginal inhibition of [H-3]SP binding to NK-1R in guinea pig lung membra nes (K-i > 2 mu M). In hamster trachea, ZM253,270 competitively antago nized 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 binding assays in cloned receptors combined with functional receptor assays in airway s mooth muscles, demonstrate that the nonpeptide antagonist ZM253,270 is selective for the NK2 receptor species that are prevalent in hamster, compared with those found in human tissues.