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 muscarinic M(3) receptors were established and compared to binding affinities for bovine cardiac M(2) and functional affinities for guinea-pig tracheal 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 data. It was found that the M(2)-selective antagonist AQ-RA 741 showed similar 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 5945 displayed functional affinities that were similarly high in bovine and guinea-pig trachea (8.16-8.24) and approximately a 100-fold lower in bovine and guinea-pig heart (6.15-6.36); with this compound, the binding affinity in bovine cardiac membranes (6.92) was clearly higher than the functional affinity, as has meanwhile also been reported for the guinea-pig. With the M(3)-selective muscarinic antagonists p-fluorohexahydrosiladifenidol and UH-AH 371, affinities towards bovine tracheal muscarinic M(3) receptors were 0.3 log units higher than in guinea-pig 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, especially AQ-RA 741 in bovine trachea and p-fluorohexahydrosiladifenidol in bovine and guinea-pig trachea, the M(3) receptor affinities found here correlated better to the reported M(1) than to the M(3) receptor affinities. It is concluded that small, but occasionally clear species and tissue differences exist with regard to the affinities of muscarinic receptor antagonists for smooth muscle M(3) receptors, and it is suggested that this may be due to small, but potentially important differences in their amino acid sequences.