Exploration of natural and synthetic N-alkyl amides as source for new cannabinoid receptor type-2 (CB2) selective ligands

Abstract

We recently reported that certain anti-inflammatory N-alkyl amides from purple coneflower (Echinacea spp.) constitute a new class of cannabinomimetics, which selectively bind to and activate the cannabinoid type-2 (CB2) receptor [1]. In the present study, we have investigated whether chain length and substitution of the headgroup of this class of natural products can result in new compounds with nM affinities to CB2 receptors. More than 30 N-alkyl amide derivatives were synthesized. A comparison of the preliminary structure-activity relationship of N-alkyl amides with the endogenous cannabinoid arachidonoyl ethanolamine (anandamide) clearly indicates that these compounds are different pharmacophores. Moreover, unlike anandamide, N-alkyl amides and 2-arachidonoyl glycerol (2-AG) trigger CB2-receptor dependent intracellular calcium transients in myelo-monocytic cells. In dodecanoic acid derivatives, the 2E,4E double bonds were found to be crucial for optimal binding to CB2 while only the 2E double bond appears to be required for the moderate CB1 affinity. The most active compounds were isobutylamides (Ki ˜ 60 nM). We show that certain derivatives segregate and form micelles, which are no longer able to interact with the receptor. Thus, the self-assembling of these compounds directly influences CB2 affinity.