Synthesis of new cardioselective M2 muscarinic receptor antagonists

A series of 5H-dibenz[b,f]azepine derivatives was prepared and evaluated for binding affinities to muscarinic receptors in vitro. Among them, compound 8 showed a high affinity for human recombinant M-2 receptors (K-1 = 2,6 nM), a low affinity for M-4 receptors (39-fold less than for M-2 receptors) and a very low affinity for M-1 and M-3 receptors (119- and 112-fold less than for M-2 receptors, respectively). The high M-2 selectivity of 8 may be attributed to the olefinic bond of the azepine ring. Functional experiments showed 8 to be a competitive antagonist with high affinity to the cardiac (pA(2)=7.1) and low affinity to the intestinal muscarinic receptors (IC50=0.54 muM). In vivo experiments confirmed the in vitro M-2 selectivity of 8. Acetylcholine-induced bradycardia was dose-dependently antagonized in rats after both intravenous and intraduodenal administration of 8, In rats, cholinergic functions mediated by M-1 or M-3 receptors (salivary secretion, pupil diameter, gastric emptying, intestinal transit time) were not affected by the oral administration of 8 even at doses as high as 30 times the antibradycardic effective dose, Furthermore, 8 had no analgesic activity in mire, indicating poor central nervous system penetration, In dogs, nocturnal bradycardia was dose-dependently inhihited by the oral route with a duration of action of about 24 h. Compound 8 appears to be a promising cardioselective antimuscarinic agent for the treatment of dysfunctions of the cardiac conduction system such as sinus or nodal bradycardia ("sick-sinus syndrome") and atrioventricular block.