V. Bezuglov et al. / Bioorg. Med. Chem. Lett. 11 (2001) 447±449
449
activity was also reduced after administration of DHA-
DA and EPA-DA at a dose of 10 mg/kg (15%, P<0.01
and 42%, P<0.05 of the control, respectively) while
grooming behavior was again completely suppressed.
ckaert, G. A.; Maddin, C. S.; Berman, E. F.; Bohne, R. L.;
Cupps, T. L.; Milstein, J. R. J. Med. Chem. 1993, 36, 2595.
11. Di Marzo, V.; Bisogno, T.; De Petrocellis, L.; Melck, D.;
Martin, B. R. Curr. Med. Chem. 1999, 6, 721.
12. Boger, D. L.; Patterson, J. E.; Guan, X.; Cravatt, B. F.;
Lerner, R. A.; Gilula, N. B. Proc. Natl. Acad. Sci. U.S.A.
1998, 95, 4810.
To elucidate whether the cannabimimetic properties of
PUFA-DA are mediated via CB1 cannabinoid recep-
tors, experiments on the displacement of CB1-antago-
nist [3H]SR141716A from rat brain membranes were
performed as previously described.21 Among the com-
pounds tested, AA-DA and EPA-DA were the most
active (Table 1).22
13. Bezuglov, V. V.; Manevich, Y.; Archakov, A. V.; Bobrov,
M. Yu.; Kuklev, D. V.; Petrukhina, G. N.; Makarov, V. A.;
Buznikov, G. A. Russ. J. Bioorg. Chem. 1997, 23, 211.
14. Kuklev, D. V.; Popkov, A. A.; Kasyanov, S. P.; Akulin,
V. N.; Bezuglov, V. V. Russ. J. Bioorg. Chem. 1996, 22, 192.
15. The general procedure of PUFA-DA synthesis was as fol-
lows. To a solution of fatty acid in CH3CN at 0±4 ꢀC freshly
distilled triethylamine (1.4 equiv) and iso-butylchloroformate
(1.2 equiv) were added under stirring in argon atmosphere.
After 30±40 min the mixture was evaporated to dryness. The
resulting mixed anhydride was treated with a solution of 1.1
equiv of 3-hydroxytyramine hydrochloride in DMF contain-
ing 1.1 equiv of Et3N for 18 h at +4 ꢀC under argon. The
mixture was diluted with water and extracted with ethyl ace-
tate. The organic extracts were washed with water and brine,
dried over sodium sulfate and concentrated under vacuum.
Finally, the compounds were isolated by column chromato-
graphy. The products were characterized by 1H and 13C
NMR, and corresponding satisfactory UV and mass spectra
were obtained. Details may be provided upon request.
16. Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis 1973, 487.
17. It was reported recently, that the `mixed anhydride' proce-
dure did not provide a satisfactory yield of 3-hydroxytyramides
of linoleic and some other fatty acids.18 In our hands this pro-
cedure gives good yields of the target compounds, so we did not
search for more sophisticated coupling methods such as those
using peptide chemistry reagents like BOP18 or others.
18. Czarnocki, Z.; Matuszewska, M. P.; Matuszewska, I. Org.
Prep. Proc. Int. 1998, 30, 585.
Our data demonstrate that amides of PUFAs with
dopamine possess pronounced cannabimimetic proper-
ties, especially if the fatty acid moiety contains four or
more double bonds. This suggests that these compounds
should be added to the family of CB1-cannabinoid
receptor agonists. The interaction of these molecules
with the dopaminergic system as well as other biochem-
ical properties of PUFA-DA were described elsewhere. 23
Acknowledgements
Partial support by INTAS (No. 96-0987), Russian
Foundation for Basic Research (No. 99-04-48514 and
No. 00-04-81087), bilateral CNR-RAS support (to
MYB No. 09) and MURST(to VDM, No. 3933) is
acknowledged.
References and Notes
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compound, observed in the tetrad of tests does not necessarily
correlate with high anity for CB1 receptors. For instance, it
was shown that oleamide is not a CB1 or CB2 receptor ligand
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