This work reports the design and synthesis of novel alkylamides, characterized by a dibenzo-
[a,d]cycloheptene nucleus, as melatonin (MLT) receptor ligands. The tricyclic scaffold was chosen
on the basis of previous quantitative structure-activity studies on MT1 and MT2 antagonists,
relating selective MT2 antagonism to the presence of an aromatic substituent out of the plane
of the MLT indole ring. Some dibenzo seven-membered structures were thus selected because
of the noncoplanar arrangement of their benzene rings, and an alkylamide chain was introduced
to fit the requirements for MLT receptor binding, namely, dibenzocycloheptenes with an
acylaminoalkyl side chain at position 10 and dibenzoazepines with this side chain originating
from the nitrogen atom bridging the two phenyl rings. Binding affinity at human cloned MT1
and MT2 receptors was measured by 2-[125I]iodomelatonin displacement assay and intrinsic
activity by the GTPgS test. The majority of the compounds were characterized by higher affinity
at the MT2 than at the MT1 receptor and by very low intrinsic activity values, thus confirming
the importance of the noncoplanar arrangement of the two aromatic rings for selective MT2
antagonism. Dibenzocycloheptenes generally displayed higher MT1 and MT2 affinity than
dibenzoazepines. N-(8-Methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylmethyl)propionamide
(4c) and -butyramide (4d) were the most selective MT2 receptor antagonists of the
series, with MT2 receptor affinity comparable to that of melatonin and as such among the
highest reported in the literature for MLT receptor antagonists. The acetamide derivative 4b
produced a noticeable reduction of GTPgS binding at MT2 receptor, thus being among the few
inverse agonists described
