Synthesis of new cardioselective M2 muscarinic receptor antagonists

Article abstract of DOI:10.1248/cpb.48.1611

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 M₂ receptors (K(i)=2.6 nM), a low affinity for M₄ receptors (39-fold less than for M₂ receptors) and a very low affinity for M₁ and M₃ receptors (119- and 112-fold less than for M₂ receptors, respectively). The high M₂ 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 (pA₂=7.1) and low affinity to the intestinal muscarinic receptors (IC₅₀=0.54 μM). In vivo experiments confirmed the in vitro M₂ 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 M₁ or M₃ 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 mice, indicating poor central nervous system penetration. In dogs, nocturnal bradycardia was dose-dependently inhibited by the oral route with a duration of action of about 24h. 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.

Full text of DOI:10.1248/cpb.48.1611

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