Exploration of natural alkylamides and synthetic analogs as source for new ligands for the cannabinoid type-2 receptor

Abstract

The cannabinoid type-2 (CB2) receptor is an attractive target for the development of drugs against inflammatory disease, atherosclerosis, and osteoporosis. Based on the discovery that alkylamides (alkamides) from Echinacea constitute a new class of CB2-specific cannabinomimetics1, we have screened a series of synthetic analogs of Echinacea alkylamides as well as other plant-derived natural N-alkyl amides for competitive binding to the CB2-receptor. Because dodeca-2E,4E-dienoic acid isobutylamide from Echinacea has a high affinity to the human CB2-receptor we synthesized analogs with modified head groups, as reported for the endogenous cannabinoid anandamide2. The resulting preliminary structure-activity relationship clearly shows that the CB2 receptor binding mode of Echinacea alkylamides is different from anandamide. To further explore the potential of natural N-alkyl amides as a new general class of CB2 ligands we have initiated a screening of plant extracts. The hexane extracts of the medicinal plants Spilanthes oleracea L. and Lepidium meyenii Walper. which are known to contain distinct types of alkylamides, were tested in receptor binding assays. The alkylamide-fraction of the L. meyenii extract showed significant receptor binding and five isolated benzylated alkylamides (macamides) were assessed for both their CB2-receptor affinity as well as CB2-mediated functional effects. Our data show that natural alkylamides from Echinacea and Lepidium are promising candidates for the development of novel CB2-receptor ligands.