1470
B. M. Smith et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1467–1470
has a slightly lower 5-HT2C potency compared to 15 and
lower selectivity.
of 3-benzazepines was designed. This series has provided
a number of potent and selective 5-HT2C receptor agon-
ists which are orally active in an acute feeding model in
Sprague–Dawley rats. Further studies have resulted in
the identification and advancement of one compound
from this series into human clinical trials.
Adding a 7-position substituent to 15 increases 5-HT2C
potency as seen with compounds 18b and 18d (compare
also compound 8), but an even greater increase in 5-
HT2A and 5-HT2B receptor potencies results in reduced
selectivities. In contrast, the 8,9-disubstituted benzaze-
pines 18c and e, show significant improvement in recep-
tor selectivity compared to 15, with 5-HT2C potency
slightly increased for 18c, and decreased for 18e. Upon
comparison of the enantiomers of 15 with the enantio-
mers of 18c, unexpected results were obtained. It can
be seen that (R)-15, (S)-15 and 1915 are all of similar po-
tency and selectivity. A slight advantage in 5-HT2C po-
tency for (R)-15 and 19 over (S)-15 is observed and a
slight advantage in 5-HT2A selectivity is observed for
(R)-15 and (S)-15 over 19. In comparison,(S)-18c is
about 70-fold more potent at the 5-HT2C receptor than
(R)-18c, which represents not only a change in magni-
tude, but also a switch in preferred stereochemistry.
Also of interest is the drop in 5-HT2A maximal response,
relative to the serotonin control, observed for (S)-18c. In
all previous cases, compounds have been full, or nearly
full agonists at the three receptors. The 5-HT2C and 5-
HT2B responses have all been in the 90–100% range.
The 5-HT2A responses have occasionally dipped to
70%. For (S)-18c, the 5-HT2A maximal response is only
35%, and for the 5-HT2B receptor only 25% response is
observed at the highest test concentration of 10 uM. In
this case, we believe that a steric interaction between
the (S)-1-methyl and 9-chloro substituents further locks
the seven-membered ring into a conformation favorable
to 5-HT2C receptor activation and less favourable to
either 5-HT2A or 5-HT2B activation. In contrast, the
interaction between the (R)-1-methyl and 9-chloro sub-
stituents of (R)-18c locks the seven-membered ring into
a conformation less favourable to activation of all three
receptors.
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Using structural features from known 5-HT2C agonists
and incorporating these into a rigid framework, a series