SELECTIVITY PROFILE OF SOME RECENT MUSCARINIC ANTAGONISTS IN BOVINE AND GUINEA-PIG TRACHEA AND HEART

The functional affinities of some recently developed subtype-selective muscarinic antagonists towards bovine tracheal smooth muscle muscarin ic M(3) receptors were established and compared to binding affinities for bovine cardiac M(2) and functional affinities for guinea-pig trach eal smooth muscle M(3) receptors; functional affinities towards bovine or guinea-pig cardiac M(2) receptors were determined when the M(2)/M( 3) selectivity in bovine tissues deviated from reported guinea-pig dat a. It was found that the M(2)-selective antagonist AQ-RA 741 showed si milar high affinities in bovine and guinea-pig heart (8.27-8.41); the affinity in bovine trachea, however, was almost 10-fold higher than in guinea-pig trachea (7.51-6.63). The M(3)-selective antagonist DAC 594 5 displayed functional affinities that were similarly high in bovine a nd guinea-pig trachea (8.16-8.24) and approximately a 100-fold lower i n bovine and guinea-pig heart (6.15-6.36); with this compound, the bin ding affinity in bovine cardiac membranes (6.92) was clearly higher th an the functional affinity, as has meanwhile also been reported for th e guinea-pig. With the M(3)-selective muscarinic antagonists p-fluoroh exahydrosiladifenidol and UH-AH 371, affinities towards bovine trachea l muscarinic M(3) receptors were 0.3 log units higher than in guinea-p ig trachea (7.36-7.09 and 8.43-8.13, respectively), and, in case of p- fluorohexahydrosiladifenidol, both were lower than previously reported for the guinea-pig ileum (typically 7.8). In some instances, especial ly AQ-RA 741 in bovine trachea and p-fluorohexahydrosiladifenidol in b ovine and guinea-pig trachea, the M(3) receptor affinities found here correlated better to the reported M(1) than to the M(3) receptor affin ities. It is concluded that small, but occasionally clear species and tissue differences exist with regard to the affinities of muscarinic r eceptor antagonists for smooth muscle M(3) receptors, and it is sugges ted that this may be due to small, but potentially important differenc es in their amino acid sequences.