RT Journal Article
SR Electronic
T1 Pharmacological characterization of a new class of nonpeptide neurokinin A antagonists that demonstrate species selectivity.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1216
OP 1221
VO 274
IS 3
A1 D Aharony
A1 C K Buckner
A1 J L Ellis
A1 S V Ghanekar
A1 A Graham
A1 J S Kays
A1 J Little
A1 S Meeker
A1 S C Miller
A1 B J Undem
YR 1995
UL http://jpet.aspetjournals.org/content/274/3/1216.abstract
AB We examined the pharmacology of ZM253,270 and two representative examples of the pyrrolopyrimidines, a new class of nonpeptide, 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 less potent analogs of ZM253,270. The pyrrolopyrimidines demonstrated only marginal inhibition of [3H]SP binding to NK-1R in guinea pig lung membranes (Ki > 2 microM). In hamster trachea, ZM253,270 competitively antagonized the contractile response evoked by neurokinin A (NKA, -logKB = 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 smooth 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.