A series of 5H-dibenz[b,f]azepine derivatives was prepared and evaluated fo
r 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) a
nd a very low affinity for M-1 and M-3 receptors (119- and 112-fold less th
an for M-2 receptors, respectively). The high M-2 selectivity of 8 may be a
ttributed 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. A
cetylcholine-induced bradycardia was dose-dependently antagonized in rats a
fter both intravenous and intraduodenal administration of 8, In rats, choli
nergic functions mediated by M-1 or M-3 receptors (salivary secretion, pupi
l diameter, gastric emptying, intestinal transit time) were not affected by
the oral administration of 8 even at doses as high as 30 times the antibra
dycardic effective dose, Furthermore, 8 had no analgesic activity in mire,
indicating poor central nervous system penetration, In dogs, nocturnal brad
ycardia 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 cond
uction system such as sinus or nodal bradycardia ("sick-sinus syndrome") an
d atrioventricular block.