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A. Tsotinis et al. / Il Farmaco 56 (2001) 725–729
absence of the 5-methoxyl group in tryptamine deriva-
tives, as in luzindole [27], or in 4-phenyl substituted
tetralines, as in 4-phenyl-2-acetylaminotetralin [28],
leads to antagonism. We attribute the difference in
agonist/antagonist behavior between analogs 4–8 and
9–13 to a combination of stereoelectronic effects ex-
erted by both the methoxyl group, where present, and
the cyclohexane ring, annulated between N1 and C2 of
the indole nucleus. This argument is reinforced by our
earlier observations on compounds 2, which, as men-
tioned previously, instead of a cyclohexane ring bear a
tetralin moiety annulated between N1 and C2 [20].
In conclusion, the compounds reported herein are the
first examples that utilize a fused cyclohexane at the
lower N1-C2 region of the melatonin skeleton in order
to probe the constraints at the receptor site. As these
preliminary results merit further investigation we are
currently engaged with the synthesis and biological
evaluation of a new series of tricyclic compounds.
sponses to melatonin. The concentration of analog
producing 50% of the maximum agonist response
(EC50) was determined from concentration–response
curves. For evaluation of antagonist potency, cells were
treated with vehicle (1% DMSO or methanol) or vary-
ing concentrations (10−4 to 10−9 M) of the analogs for
60 min before melatonin (10−9 M) was added. The
concentration of analog reducing melatonin-induced
pigment aggregation by 50% (IC50) was determined.
Acknowledgements
Ms Sachi Sivanthan would like to thank the Nuffield
Foundation Undergraduate Research Bursary for
financial support.
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Comp.
R5
R
Agonist
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(pEC50
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Melatonin
Luzindole
10.07
NA a
5.61
4
5
6
7
8
H
H
H
H
H
CH3
C2H5
C3H7
NA
NA
NA
3.75
4.24
3.43
3.71
3.22
c-C3H5 NA
c-C4H7 NA
9
OCH3 CH3
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9.29
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a NA, no agonist or antagonist effect detected at 100 mM. Agonist
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