The pharmacology of cannabinoid receptors and their ligands: an overview

Abstract

Mammalian tissues express at least two cannabinoid receptor types, CB 1 and CB 2 , both G protein coupled. CB 1 receptors are found predominantly at nerve terminals where they mediate inhibition of transmitter release. CB 2 receptors occur mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous agonists for cannabinoid receptors also exist, and are all eicosanoids. The first-discovered of these 'endocannabinoids' was arachidonoylethanolamide and there is convincing evidence that this ligand and some of its metabolites can activate vanilloid VRI (TRPV1) receptors. Certain cannabinoids also appear to have TRPV1-like and/or non-CB 1 , non-CB 2 , non-TRPV1 targets. Several CB 1 -and CB 2 -selective agonists and antagonists have been developed. Antagonists include the CB 1 -selective SR141716A, AM251, AM281 and LY320135, and the CB 2 -selective SR144528 and AM630. These all behave as inverse agonists, one indication that CB 1 and CB 2 receptors can exist in a constitutively active state. 'Neutral' cannabinoid receptor antagonists have also been developed. CB 1 and/or CB 2 receptor activation appears to ameliorate inflammatory and neuropathic pain and certain multiple sclerosis symptoms. This might be exploited clinically by using CB 1 , CB 2 or CB 1 /CB 2 agonists, or inhibitors of the membrane transport or catabolism of endocannabinoids that are released in increased amounts, at least in animal models of pain and multiple sclerosis. We have recently discovered the presence of an allosteric site on the CB 1 receptor. Consequently, it may also prove possible to enhance 'autoprotective' effects of released endocannabinoids with CB 1 allosteric enhancers or, indeed, to reduce proposed 'autoimpairing' effects of released endocannabinoids such as excessive food intake with CB 1 allosteric antagonists.

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

“…Our above data suggest that 2-AG, which acts at CB 1 R but not TRPV1 receptors (43), possibly controls cell sorting in immature pancreatic islets. This notion prompted us to determine whether CB 1 R loss of function alters the microarchitecture of mouse pancreatic islets in vivo.…”

“…AEA and 2-AG exhibit remarkably different receptor specificities: Whereas both 2-AG and AEA bind CB 1 /CB 2 cannabinoid receptors, only AEA activates TRPV1 channels (43,60). We took advantage of this receptor selectivity when combining an in vitro model of ordered α-and β-cell aggregation with mouse genetics.…”

“…4F1). Subsequently, we exposed pseudoislets to AEA, a mixed eCB/endovanilloid ligand that acts as an agonist at both CB 1 Rs and TRPV1s (43). AEA significantly increased pseudoislet diameter [13, (Fig.…”

The endocannabinoid system as a link between homoeostatic and hedonic pathways involved in energy balance regulation

“…Brain CB 1 receptors are coupled, among other things, to neurotransmitter release inhibition, whereas CB 2 receptors participate in the regulation of cytokine release and immune cell function. 2 The discovery of CB 1 and CB 2 receptors led to the finding of endogenous compounds capable of binding to and activating them: the endocannabinoids (ECs). The two best-studied ECs are N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) ( Figure 1).…”

Modulation of the endocannabinoid system: Therapeutic potential against cocaine dependence

“…During the last decade researchers have provided evidence for the existence of at least two cannabinoid receptors, CB1 and CB2 (36,37,38,39) and we have now available different selective synthetic agonists and antagonists for both CB1 and CB2 receptors (40,41), other than classic, plant-derived cannabinoid agonists like delta-9-THC, the active ingredient in marijuana. Although the existence of novel cannabinoid receptors has been suggested in different studies (42,43,44), definitive proof of the existence of these cannabinoid receptors has yet to be shown.…”