4606
F. Li et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4603–4606
Table 2
and Technology (07pj14104), and grants from the State Key Labo-
Emax/EC50 values for the stimulation of [35S]GTP S binding by novel compoundsa
c
ratory of Drug Research, Shanghai Institute of Materia Medica
(SIMM0809KF-02). We also thank Dr Yan Zhang from Department
of Medicinal Chemistry, Virginia Commonwealth University for
valuable discussion.
Compd
l
(mean SE)
j
(mean SE)
d (mean SE)
EC50 (nM)/Emax (%)
EC50 (nM)/Emax (%)
EC50 (nM)/Emax (%)
7b
7c
173.9 26.8/95.7 2.9
33.0 10.0/88.6 1.2
62.1 13.5/76.2 1.2
67.1 3.0/79.9 1.4
65.0 17.0/77.3 3.2
10 0.4/91.4 1.4
a
Supplementary data
CHO membranes, expressing either the
j or l receptor, were incubated with
varying concentrations of the novel compounds in the presence of 0.8 nM
35S]GTP
S. Data are the mean values (SE from three experiments, performed in
triplicate.
[
c
Supplementary data associated with this article can be found, in
References and notes
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ity at all the opioid receptors. The N-Me analog 20a shows
moderate affinity and selectivity for the d receptor, whereas the
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N-CPM analog 20b prefers the
anes 7a–d showed improved affinity and selectivity for the
receptor than their 3-MeO congeners with Kis of 40–500 nM. N-
Me indolopropellane 7a showed potency of 104 nM for the
receptor and 10-fold selectivity against both and d receptors.
Masking the indole-NH moiety with Me-group (7b) caused a 2.5-
and 4-fold improvement in binding at the and d receptors,
respectively. N-CPM analogs 7c and 7d displayed similar affinity
(523 and 469 nM) for the receptor, while indole 7c is twofold
more potent than the N-Me protected indole 7d at the receptor.
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l receptor. All 3-OH indolopropell-
l
l
j
l
l
j
l
receptor with a Ki value of 40 nM among the skeletal rearranged
morphinans series.
Compounds 7b and 7c with highest binding affinity for the
l
receptors were selected for stimulation of [35S]GTP
cS binding stud-
ies (Table 2) to determine agonistic properties. Both indolopropell-
anes 7b, c showed full agonistic activity at all three receptors.
However, in comparison to compound 7c, the higher binding of
7b at the
l receptor was not relevant to higher efficacy. The former
compound (7c) has an EC50 value of 33 nM, fivefold more potent
than the latter compound (7b).
In conclusion, a series of skeletal rearranged indolopropellanes
7a–d were obtained through a typical N-demethylation approach
of 3-methoxy-N-methyl-14-hydroxy-morphinan-6-one 12 fol-
lowed by alkylation, reduction and Fischer indole cyclization.
These novel compounds generally displayed moderate binding po-
tency and selectivity at the
in this series is compound 7b, which has Ki value of 40 nM at the
receptor, and is 6- and 25-fold more potent against d and recep-
tors, respectively. All these compounds displayed good agonistic
activity at the receptor. The different binding and receptor selec-
tivity profiles of these indolopropellanes suggest that the new pro-
l receptor. The most potent compound
l
j
l
pellane skeleton has a different binding mode favorable for the
l
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Acknowledgments
This work was supported by a Hundred Talent Project of the
Chinese Academy of Sciences, and grants from Chinese National
Science Foundation (30772625), Shanghai Commission of Science