The Pharmacology of the Cannabinoid System—A Question of Efficacy and Selectivity

Abstract

Our knowledge of the function of the cannabinoid system in the body has been aided by the availability of pharmacological agents that affect its function. This has been achieved by the design of agents that either directly interact with the receptor (agonists and antagonist/inverse agonists) and agents that indirectly modulate the receptor output by changing the levels of the endogenous cannabinoids (endocannabinoids). In this review, examples of the most commonly used receptor agonists, antagonists/inverse agonists, and indirectly acting agents (anandamide uptake inhibitors, fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors) are given, with particular focus upon their selectivity and, in the case of the directly acting compounds, efficacy. Finally, the links between the endocannabinoid and cyclooxygenase pathways are explored, in particular, with respect to agents whose primary function is to inhibit cyclooxygenase activity, but which also interact with the endocannabinoid system.

Synergistic immunomopharmacological effects of N-alkylamides in Echinacea purpurea herbal extracts

“…FAAH inhibition by herba extract and dodeca-2E,4E,8Z, 10E/Z-tetraenoic acid isobutylamide LPS stimulation of monocytes/macrophages leads to the release of endocannabinoids 2-AG and anandamide, which then activate CB receptors in an autocrine fashion [13]. We investigated whether E. purpurea tinctures are able to modulate endocannabinoid metabolism by the hydrolyzing membrane-associated homodimeric enzyme fatty acid amide hydrolase (FAAH), which is known to be the enzyme responsible for the degradation of anandamide but also 2-AG [21]. While no effects were observed on monoacyl glycerol lipase (MAGL) (data not shown), which is another enzyme involved in the degradation of 2-AG, the herba tincture but not the radix tincture concentration-dependently inhibited FAAH (Fig.…”

“…However, no IC 50 value could be measured, indicating that this compound is a partial inhibitor of FAAH. Since FAAH inhibitors are potentially therapeutic agents [21] the observed inhibitory effect, if translated to a physiological context, may contribute to the cannabimimetic action of E. purpurea tinctures.…”

CB1 cannabinoid receptor activation dose dependently modulates neuronal activity within caudal but not rostral song control regions of adult zebra finch telencephalon

“…Rimonabant is a problematic antagonist. In some systems (and in most behavioral systems), it appears to function as a true CB 1 -selective antagonist (Fowler 2007). In other systems, particularly those in vitro, it clearly has the ability to function as an inverse agonist (reviewed by Pertwee 2005).…”

Peripheral Metabolic Effects of Endocannabinoids and Cannabinoid Receptor Blockade

“…FAAH inhibitors, but most of them will directly or indirectly activate cannabinoid receptors in order to modulate chronic inflammation and pain disorders. Again, the development of drugs with only peripheral actions to avoid central side effects is preferred [85,86]. Second, the peripheral metabolic effects described in this review ( fig.…”