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doi:10.1016/j.bmc.2007.05.060 
Copyright © 2007 Elsevier Ltd All rights reserved.
Design, synthesis, binding, and molecular modeling studies of new potent ligands of cannabinoid receptors
Antonella Brizzia, 
, 
, Maria Grazia Casciob, c, Vittorio Brizzia, Tiziana Bisognob, Maria Teresa Dinatoloa, Adriano Martinellid, Tiziano Tuccinardid and Vincenzo Di Marzob
Received 7 February 2007;
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Abstract
In our ongoing program aimed at the design, synthesis, and biological evaluation of novel cannabinoid receptor ligands derived from olivetol and hexyl-resorcinol, we have designed a structural model for new derivatives on the basis of a previous study. Here we report the synthesis, binding, and molecular modeling studies of new potent compounds with high affinity toward CB1 and CB2 receptors. Compounds with amidic ‘heads’ with alkyloxy chains varying in length from 8 to 12 carbon atoms showed nanomolar affinity for both receptors, depending on the type of aromatic backbone. Two of the new compounds, although not very potent, exhibit selectivity for CB1 receptors (CB1/CB2 = 0.07 and 0.08, respectively). Molecular modeling studies fitted this new class of cannabinoid ligands into a CB1 receptor model, and the qualitative analysis of the results was in general agreement with the CB1 affinity constants observed experimentally for these derivatives.
Keywords: Anandamide; Endocannabinoids; Cannabinoid receptors; Docking
Article Outline
- 1. Introduction
- 2. Chemistry
- 3. Pharmacological evaluation
- 4. Results and discussion
- 4.1. Molecular modeling
- 5. Conclusions
- 6. Experimental
- 6.1. General information
- 6.2. General method for esters
- 6.3. General methods for the final products
- 6.3.1. Method A
- 6.3.2. Method B
- 6.3.3. 8-(3-Hydroxy-5-pentyl-phenoxy)-octanoic acid (2-hydroxy-ethyl)-amide (10)
- 6.3.4. 8-(3-Hydroxy-5-pentyl-phenoxy)-octanoic acid cyclopropylamide (11)
- 6.3.5. 11-(3-Hydroxy-5-pentyl-phenoxy)-undecanoic acid cyclopropylmethyl-amide (12)
- 6.3.6. 11-(3-Hydroxy-5-pentyl-phenoxy)-undecanoic acid [2-(3,4-dihydroxy-phenyl)-ethyl]-amide (13)
- 6.3.7. 11-(3-Hydroxy-5-pentyl-phenoxy)-undecanoic acid (3-methoxy-4-hydroxy-phenyl)-amide (14)
- 6.3.8. 12-(3-Hydroxy-5-pentyl-phenoxy)-dodecanoic acid (2-hydroxy-ethyl)-amide (15)
- 6.3.9. 12-(3-Hydroxy-5-pentyl-phenoxy)-dodecanoic acid cyclopropylamide (16)
- 6.3.10. 8-(2-Hexyl-5-hydroxy-phenoxy)-octanoic acid (2-hydroxy-ethyl)-amide (17)
- 6.3.11. 8-(2-Hexyl-5-hydroxy-phenoxy)-octanoic acid cyclopropylamide (18)
- 6.3.12. 11-(2-Hexyl-5-hydroxy-phenoxy)-undecanoic acid cyclopropylmethyl-amide (19)
- 6.3.13. 11-(2-Hexyl-5-hydroxy-phenoxy)-undecanoic acid [2-(3,4-dihydroxy-phenyl)-ethyl]-amide (20)
- 6.3.14. 11-(2-Hexyl-5-hydroxy-phenoxy)-undecanoic acid (3-methoxy-4-hydroxy-phenyl)-amide (21)
- 6.3.15. 12-(2-Hexyl-5-hydroxy-phenoxy)-dodecanoic acid (2-hydroxy-ethyl)-amide (22)
- 6.3.16. 12-(2-Hexyl-5-hydroxy-phenoxy)-dodecanoic acid cyclopropylamide (23)
- 6.3.17. 8-(4-Hexyl-3-hydroxy-phenoxy)-octanoic acid (2-hydroxy-ethyl)-amide (24)
- 6.3.18. 8-(4-Hexyl-3-hydroxy-phenoxy)-octanoic acid cyclopropylamide (25)
- 6.3.19. 11-(4-Hexyl-3-hydroxy-phenoxy)-undecanoic acid cyclopropylmethyl-amide (26)
- 6.3.20. 11-(4-Hexyl-3-hydroxy-phenoxy)-undecanoic acid [2-(3,4-dihydroxy-phenyl)-ethyl]-amide (27)
- 6.3.21. 11-(4-Hexyl-3-hydroxy-phenoxy)-undecanoic acid (3-methoxy-4-hydroxy-phenyl)-amide (28)
- 6.3.22. 12-(4-Hexyl-3-hydroxy-phenoxy)-dodecanoic acid (2-hydroxy-ethyl)-amide (29)
- 6.3.23. 12-(4-Hexyl-3-hydroxy-phenoxy)-dodecanoic acid cyclopropylamide (30)
- 6.4. Molecular modeling
- Acknowledgements
- References
1 μM) are highlighted in bold as well as the most selective compounds for CB1 and CB2. Standard errors are not shown for the sake of simplicity and were never higher than 10% of the means.