New resorcinol-anandamide "hybrids" as potent cannabinoid receptor ligands endowed with antinociceptive activity in vivo

Antonella Brizzi*, Vittorio Brizzi, Maria Grazia Cascio, Federico Corelli, Francesca Guida, Alessia Ligresti, Sabatino Maione, Adriano Martinelli, Serena Pasquini, Tiziano Tuccinardi, Vincenzo Di Marzo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


Bearing in mind the pharmacophoric requirements of both (-)-trans-Δ 9-tetrahydrocannabinol (THC) and anandamide (AEA), we designed a novel pharmacophore consisting of both a rigid aromatic backbone and a flexible chain with the aim to develop a series of stable and potent ligands of cannabinoid receptors. In this paper we report the synthesis, docking studies, and structure-activity relationships of new resorcinol-anandamide "hybrids" differing in the side chain group. Compounds bearing a 2-methyloctan-2-yl group at position 5 showed a significantly higher affinity for cannabinoid (CB) receptors, in particular when an alkyloxy chain of 7 or 10 carbon atoms was also present at position 1. Derivative 32 was a potent CB 1 and CB 2 ligand, with K i values similar to that of WIN 55-212 and potent antinociceptive activity in vivo. Moreover, derivative 38, although less potent, proved to be the most selective ligand for CB 2 receptor (K i(CB 1)) 1 μM, K i(CB 2)) 35 nM).

Original languageEnglish
Pages (from-to)2506-2514
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number8
Early online date30 Mar 2009
Publication statusPublished - 23 Apr 2009

Bibliographical note

Acknowledgement: The authors from the University of Siena thank the Ministero dell’Università e della Ricerca (PRIN 2006, Prot. n 2006030948_002) for financial support. Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH Grant P41 RR-01081). The authors are grateful to Marco Allarà for technical assistance with the binding assays.


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