anandamide and resorcinol

In our ongoing program aimed at deeply investigating the endocannabinoid system (ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the importance of the carboxamide functionality. Binding studies on CB1 and CB2 receptors, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds behaved as very potent cannabinoid receptor ligands (Ki in the nanomolar range) while, however, none of them was able to inhibit MAGL and/or FAAH. Derivative 11 was a potent CB1 and CB2 ligand, with Ki values similar to WIN 55,212, exhibiting a CB1 and CB2 agonist profile in vitro. In the formalin test of peripheral acute and inflammatory pain in mice, this compound showed a weak and delayed antinociceptive effect against the second phase of the nocifensive response, exhibiting, interestingly, a quite potent transient receptor potential ankyrin type-1 (TRPA1) channel agonist activity. Moreover, derivative 14, characterized by lower affinity but higher CB2 selectivity than 11, proved to behave as a weak CB2 competitive inverse agonist.

Topics: Analgesics; Animals; Calcium Channels; Cell Survival; Cells, Cultured; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Humans; Ligands; Male; Mice; Molecular Structure; Nerve Tissue Proteins; NIH 3T3 Cells; Nociception; Pain; Pain Measurement; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Resorcinols; Structure-Activity Relationship; Transient Receptor Potential Channels; TRPA1 Cation Channel

Bearing in mind the pharmacophoric requirements of both (-)-trans-Delta(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 muM, K(i)(CB(2)) = 35 nM).

Topics: Analgesics; Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Chlorocebus aethiops; COS Cells; Drug Partial Agonism; Endocannabinoids; Humans; Ligands; Mice; Models, Molecular; Pain Measurement; Phenols; Polyunsaturated Alkamides; Radioligand Assay; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Resorcinols; Stereotyped Behavior; Structure-Activity Relationship