D. P. Papahatjis et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3583–3586
3585
3. For a review on the cannabinoid receptors, see: Pertwee,
R. G. Pharmacol. Ther. 1997, 74, 129.
Table 1. Affinities (Ki) of cannabinoid analogues 4a, 4b, 4c and 5a,
5b, 5c for the CB1 and CB2 receptors
4. (a) Makriyannis, A.; Rapaka, R. S. Life Sci. 1990, 47, 2173.
(b) Razdan, R. K. Pharmacol. Rev. 1986, 38, 21. (c) Kha-
nolkar, A. D.; Palmer, S. L.; Makriyannis, A. Chem. Phys.
Lipids 2000, 108, 37.
Compd
CB1 (Ki, nM)a
CB2 (Ki, nM)a
1a5c
1b4c
1c6
2a16
2c6
4a
4b
4c
5a
5b
47.6
0.83
0.32
1265
39.3
0.49
0.52
230
5. (a) Adams, R.; Harfenist, M.; Lowe, S. J. Am. Chem. Soc.
1949, 71, 1624. (b) Huffman, J. W.; Liddle, J.; Duncan, S. G.,
Jr.; Yu, S.; Martin, B. R.; Wiley, J. L. Bioorg. Med. Chem.
1998, 6, 2383. (c) Busch-Petersen, J.; Hill, W. A.; Fan, P.;
Khanolkar, A.; Xie, X. Q.; Tius, M. A.; Makriyannis, A.
J. Med. Chem. 1996, 39, 3790. (d) Khanolkar, A. D.; Lu, D.;
Fan, P.; Tian, X.; Makriyannis, A. Bioorg. Med. Chem. Lett.
1999, 9, 2119. (e) Martin, B. R.; Jefferson, R.; Winckler, R.;
Wiley, J. L.; Huffman, J. W.; Crocker, P. J.; Saha, B.; Razdan,
R. K. J. Pharmacol. Exp. Ther. 1999, 290, 1065. (f) Singer, M.;
Ryan, W. J.; Saha, B.; Martin, B. R.; Razdan, R. K. J. Med.
Chem. 1998, 41, 4400.
136
50
59 (ꢂ7)
665 (ꢂ161)
189 (ꢂ29)
0.44 (ꢂ0.07)
1.27 (ꢂ0.27)
0.71 (ꢂ0.21)
99 (ꢂ15)
33 (ꢂ9)
63 (ꢂ16)
0.86 (ꢂ0.16)
0.29 (ꢂ0.06)
1.0 (ꢂ0.36)
5c
aKi values of the cannabinoid analogues were obtained from three
independent experiments run in duplicate and are expressed as the
mean of three values, standard deviation is given in parentheses.
6. Papahatjis, D. P.; Kourouli, T.; Abadji, V.; Goutopoulos,
A.; Makriyannis, A. J. Med. Chem. 1998, 41, 1195.
7. Petrzilka, T.; Haeflinger, W.; Sikemeier, C. Helv. Chim.
Acta 1969, 52, 1102.
8. Pitt, C. G.; Hobbs, D. T.; Schram, H.; Twine, C. E., Jr.;
Williams, D. L. J. Lab. Comp. 1975, 11, 551.
9. (+)-cis/trans-p-Mentha-2,8-dien-1-ol was supplied by Fir-
menich Inc., Princeton, NJ.
10. All new compounds (3a, 3b, 3c, 4a, 4b, 4c, 5a, 5b, 5c, 7, 8,
10, 11b, and 11c) were fully characterized by NMR, MS, and
HRMS spectra. Selected data of final cannabinoids:
well as the significantly bulkier C-200,200-dichloro and
dibromo groups. Our data show that the cyclopropyl
analogue 5a exhibits similar affinities for CB1 and CB2
as its gem-dimethyl prototype 1b, although the presence
of the cyclopropyl group appears to lead to slightly
enhanced selectivity for CB1. This preference is reversed
with the introduction of gem-dichloro substitution in
the cyclopropyl ring (5b). Conversely, the bulkier gem-
dibromocyclopropyl analogue (5c) has almost equal
affinities for both receptors. As expected, the canna-
bidiol analogues 2a,16 2c, and 4a–4c have affinities for
CB1 and CB2 over two orders of magnitude weaker
than the respective tetrahydrocannabinols. However,
the two series appear to exhibit similar SAR trends.
This suggests similar binding motifs for the benzylic
chain substituents at CB1 and CB2 for tetrahydro-
cannabinol and cannabidiol analogues. We conclude that
this study adds to earlier work pointing to the presence
of a CB1/CB2 subsite at the level of the benzylic side
chain carbon in the tetrahydrocannabinol and canna-
bidiol series. We have also observed some preference for
CB1 or CB2 based on the different benzylic substituents.
However, these selectivities are relatively modest and do
not allow us to identify any specific trends. These will
have to await the development of additional side chain
substituted ligands aimed at probing the stereochemical
features of this intriguing putative subsite.
4a. 1H NMR (CDCl3) d 6.30 (brs, 2H), 5.95 (brs, 1H, –OH),
5.57 (s, 1H, 2-H), 4.66 (s, 1H), 4.60 (brs, 1H, –OH), 4.55 (s,
1H), 3.83 (m, 1H, 3-H), 2.37 (td, J1=10.4 Hz, J2=4.3 Hz, 1H,
4-H), 2.26–2.06 (m, 2H, 5-H, 6-H), 1.79 (brs, 5H, 5-H, 6-H, 7-
CH3), 1.63 (s, 3H, 10-CH3), 1.47 (m, 2H, 20ꢀCH2ꢀ), 1.19
(m, 8H), 0.84 (t, J=6.1 Hz, 3H, 70-CH3), 0.71 (m, 2H, cyclo-
propyl), 0.56 (m, 2H, cyclopropyl); MS m/z (rel intensity) 368
(M+, 43), 300 (77), 285 (100), 247 (38), 229 (37), 121 (19).
Exact mass calcd for C25H36O2, 368.2715; found, 368.2710.
4b. 1H NMR (CDCl3) d 6.31 (m, 1H), 6.23 (m, 1H), 6.12
(brs, 1H, –OH), 5.60 (m, 1H, 2-H), 4.79 (brs, 1H, –OH), 4.63
(s, 1H), 4.48 (s, 1H), 3.84 (m, 1H, 3-H), 2.33 (m, 1H, 4-H),
2.21–2.10 (m, 2H, 5-H, 6-H), 2.06 (m, 1H, 20-H), 1.80 (m, 6H,
7-CH3, 5-H, 6-H, –CHCCl2), 1.60 (m, 4H, 10-CH3, 20-H), 1.45
(d, J=7.3 Hz, 1H, –CHCCl2), 1.18 (m, 8H), 0.82 (t, J=6.7 Hz,
3H, 70-CH3); MS m/z (rel intensity) 436 (M+, 100), 401 (56),
365 (52), 329 (44), 317 (92), 261 (58). Exact mass calcd for
C25H34Cl2O2, 436.1936; found, 436.1932.
4c. 1H NMR (CDCl3) d 6.28 (m, 2H), 6.10 (brs, 1H, ꢀOH),
5.61 (m, 1H, 2-H), 4.70 (brs, 1H, –OH), 4.62 (s, 1H), 4.47 (s,
1H), 3.83 (m, 1H, 3-H), 2.35 (m, 1H, 4-H), 2.21–2.05 (m, 2H,
5-H, 6-H), 2.01 (m, 1H, 20-H), 1.99 (d, J=7.3 Hz, 1H, –
CHCBr2), 1.80 (m, 5H, 7-CH3, 5-H, 6-H), 1.60 (m, 5H, 10-
CH3, 20-H, –CHCBr2), 1.17 (m, 8H), 0.82 (2t, overlapping,
3H, 70-CH3, mixture of diastereomers); MS m/z (rel intensity)
526 (M+, 40), 447 (26), 446 (28), 445 (25), 363 (34), 361 (35),
298 (40), 283 (89), 213 (100), 135 (34). Exact mass calcd for
C25H34Br2O2, 524.0926; found, 524.0920.
Acknowledgements
This work was supported by the National Hellenic
Research Foundation and by grants from the National
Institute on Drug Abuse DA03801, DA09158 and
DA07215. We also thank Joy Erickson for her technical
support.
5a. 1H NMR (CDCl3) d 6.34 (d, J=1.2 Hz, 1H), 6.19 (d,
J=1.2 Hz, 1H), 5.42 (m, 1H, 8-H), 4.62 (s, 1H, –OH), 3.18
(dd, J1=16.5 Hz, J2=4.3 Hz, 1H, 10a-H), 2.68 (m, 1H, 10a-
H), 2.14 (m, 1H), 1.90–1.77 (m, 3H), 1.69 (s, 3H, 9-CH3), 1.46
(m, 2H, 20ꢀCH2–), 1.37 (s, 3H, 6-CH3), 1.21 (m, 8H), 1.09 (s,
3H, 6-CH3), 0.84 (t, J=6.7 Hz, 3H, 70-CH3), 0.73 (m, 2H,
cyclopropyl), 0.57 (m, 2H, cyclopropyl); MS m/z (rel intensity)
368 (M+, 100), 353 (6), 325 (15), 297 (37), 285 (39), 246 (15).
Exact mass calcd for C25H36O2, 368.2715; found, 368.2708.
References and Notes
1. Devane, W. A.; Dysarz, F. A.; Johnson, M. R.; Melvin,
L. S.; Howlett, A. C. Mol. Pharmacol. 1988, 34, 605.
2. Munro, S.; Thomas, K. L.; Abu-Shaar, M. Nature 1993,
365, 61.
1
5b. H NMR (CDCl3) d 6.30 and 6.26 (d, J=1.4 Hz, 0.5H
each, mixture of diastereomers), 6.20 and 6.17 (d, J=1.4 Hz,
0.5H each, mixture of diastereomers), 5.42 (m, 1H, 8-H), 4.90