H. Bhattacharjee et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1691–1693
2. Huskey, A. J. Pain. Palliat. Care. Pharmacother. 2006, 20, 43.
1693
gem dimethyl group as a linker (compound 7) results in a CB2 selec-
tive compound with a Ki value of 1.07 nM at the CB2 receptor com-
pared to 93.66 nM at the CB1 receptor subtype (CB1/CB2 = 87.5).
The most significant effect is observed when the synthetic inter-
mediate 4 was evaluated for binding affinity. This compound
showed high binding affinity for the CB2 receptor with a Ki of
1.66 nM and exhibited a high 600-fold selectivity for the CB2
receptor. The introduction of a C10 hydroxyl or carbonyl group in
classical cannabinoids has not been extensively investigated; how-
ever, previous findings by our group11,15 and by Papahatjis and co-
workers,13 indicates that these C10 substituents reduce cannabi-
noid receptor affinity. Interestingly, results of our present study
show that the carbonyl and hydroxyl substituent at the C10 selec-
tively decrease CB1 receptor affinity without altering the CB2
receptor binding. The beneficial effect of the C10 equivalent hydro-
xyl, as well as the carbonyl, in CB2 receptor affinity may reflect: (1)
the removal of the pyran ring provides greater conformational flex-
ibility thus allowing for favourable receptor interactions; or (2) the
tri-aryl compounds possess a different binding orientation relative
to classical cannabinoids. Assuming that the hydroxyl increases
CB2 binding affinity via a specific receptor interaction, it is reason-
able to predict that one of the optical isomers of 4 should exhibit
greater CB2 affinity and selectivity. To test this hypothesis we are
currently synthesizing the optical isomers of 4.
The results of this research provide new information with re-
spect to the ligand binding pocket of the cannabinoid receptors.
The omission of the B ring, aromatization of the C ring, and substi-
tution of an aryl ring at C3 of the A ring in the classical cannabinoid
has yielded the tri-aryl core. The increased conformational flexibil-
ity of these compounds, relative to classical cannabinoids, should
provide insights into the steric constraints of the CB ligand binding
pocket. Furthermore, validation of the stereo-chemical require-
ments of the C10 hydroxyl may help identify a new ligand-amino
acid interaction in the binding pocket. The retention of binding
affinity after the abovementioned changes suggests that tri-aryl
based CB2 selective compounds may provide a novel therapeutic
inflammatory disease intervention. A detailed SAR study is cur-
rently in progress to determine the selectivity and functional activ-
ity of new compounds and optical isomers in this series.
3. Singh, J.; Budhiraja, S. Methods Find. Exp. Clin. Pharmacol. 2006, 28,
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S.; Luo, X.; Cheng, Y. X.; Yang, H.; Srivastava, S.; Zhou, F.; Brown, W.;
Tomaszewski, M.; Walpole, C.; Hodzic, L.; St-Onge, S.; Godbout, C.; Salois, D.;
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K. J. Med. Chem. 2000, 43, 3778.
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16. Selected data of final compounds; HPLC solvents: (1) 10% acetonitrile:90%
methanol:0.05% TFA; and 20% acetonitrile:80% methanol:0.05% TFA:4
yield = 79.2% (0.23 g) (Rf = 0.27; 20% EtOAc/hexanes) 1H NMR, 500 MHz
Varian, CDCl3, d 7.42 (d, J = 10.00 Hz, 2 Hz), 7.38 (d, J = 15.00 Hz, 2H), 7.36 (d,
J = 10.00 Hz, 2H), 7.29 (m, J = 24.00 Hz, 2H), 7.06 (s, 1H), 7.01 (s, 1H), 5.88 (s,
1H), 3.81 (s, 3H), MS: m/z (ESI, pos.) = 382.8 ([M+ 23]); HPLC retention time
13.166 min and 11.984 min; purity 98.60%; 5 yield = 32.2% (0.08 g) (Rf = 0.45;
20% EtOAc/hexanes) 1H NMR, 500 MHz Varian, CDCl3, d 7.84 (m, J = 12.0 Hz,
2H), 7.61 (t, J = 10.0 Hz, 3H), 7.50 (m, J = 19.5 Hz, 3H), 7.42 (d, J = 2.00 Hz, 1H),
7.30 (d, J = 2.00 Hz, 1H), 6.98 (s, 2H), MS: m/z (ESI, pos.) = 382.0 ([M+ 23]). HPLC
retention time: 14.173 min and 12.661 min; purity 98.68%; 6 yield = 29.1%
(0.41 g) (Rf = 0.27; 20% EtOAc/hexanes) 1H NMR, 500 MHz Varian, CDCl3, d 7.85
(m, J = 9.5 Hz, 2H), 7.61 (t, J = 15.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 2H), 7.41 (d,
J = 5.50 Hz, 1H), 7.30 (d, J = 2.00 Hz, 2H), 7.03 (d, J = 1.0 Hz, 1H), 7.00 (d,
J = 1.0 Hz, 1H), 5.36 (s, 1H), 3.78 (s, 3H), MS: m/z (ESI, pos.) = 382.0([M+ 23]).
HPLC retention time: 9.904 min and 8.362 min; purity 95.40%; 7 yield = 46.6%
(0.04 g) (Rf = 0.24; 10% EtOAc/hexanes) 1H NMR, 500 MHz Varian, CDCl3, d 7.40
(d, J = 1.5 Hz, 2H), 7.34 (t, J = 3.5 Hz, 1H), 7.31 (d, J = 6.0 Hz, 2H), 7.20 (m,
J = 7.5 Hz, 3H), 7.12 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 2.0 Hz,
1H), 4.84 (s, 1H), 1.69 (s, 6H); MS: m/z (ESI, pos.) = 380.7 ([M+ 23]). HPLC
retention time: 13.397 min and 12.054 min; purity 97.1%.
References and notes
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