title: Selectivity profile of some recent muscarinic antagonists in bovine and guinea-pig trachea and heart.
abstract: The functional affinities of some recently developed subtype-selective muscarinic antagonists towards bovine tracheal smooth muscle muscarinic M3 receptors were established and compared to binding affinities for bovine cardiac M2 and functional affinities for guinea-pig tracheal smooth muscle M3 receptors; functional affinities towards bovine or guinea-pig cardiac M2 receptors were determined when the M2/M3 selectivity in bovine tissues deviated from reported guinea-pig data. It was found that the M2-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 M3-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 M3-selective muscarinic antagonists p-fluorohexahydrosiladifenidol and UH-AH 371, affinities towards bovine tracheal muscarinic M3 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 M3 receptor affinities found here correlated better to the reported M1 than to the M3 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 M3 receptors, and it is suggested that this may be due to small, but potentially important differences in their amino acid sequences.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, University of Groningen, The Netherlands.
authors.forename: A F
authors.initials: AF
authors.lastname: Roffel
authors.forename: J J
authors.initials: JJ
authors.lastname: Hamstra
authors.forename: C R
authors.initials: CR
authors.lastname: Elzinga
authors.forename: J
authors.initials: J
authors.lastname: Zaagsma
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002417:Cattle; D003984:Dibenzazepines; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D018727:Muscarinic Antagonists; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010276:Parasympatholytics / Q000378:metabolism / Q000494:pharmacology*; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000378:metabolism; D013237:Stereoisomerism; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001570:Benzodiazepinones; D003984:Dibenzazepines; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D010879:Piperazines; D010880:Piperidines; D011976:Receptors, Muscarinic; C058297:4-fluorohexahydrosiladifenidol; C059904:UH-AH 37; C069054:AQ-RA 741; C070672:DAC 5945