Selectivity profile of some recent muscarinic antagonists in bovine and guinea-pig trachea and heart
Roffel, A.F.; Hamstra, J.J.; Elzinga, C.R.; Zaagsma, J.
Archives Internationales de Pharmacodynamie et de Therapie 328(1): 82-98
1994
ISSN/ISBN: 0003-9780 PMID: 7893193 Document Number: 433851
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.