Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.

Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.

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1 (7)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-in¯ammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). 2 CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5' pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca 2+ concentrations in cells over-expressing human VR1; (b) [ 14 C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [ 14 C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. 3 Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC 50 =3.2 ± 3.5 mM, and with a maximal e ect similar in e cacy to that of capsaicin, i.e. 67 ± 70% of the e ect obtained with ionomycin (4 mM). CBD (10 mM) desensitized VR1 to the action of capsaicin. The e ects of maximal doses of the two compounds were not additive. 4 (+)-5'-DMH-CBD and (+)-7-hydroxy-5'-DMH-CBD inhibited [ 14 C]-AEA uptake (IC 50 =10.0 and 7.0 mM); the (7)-enantiomers were slightly less active (IC 50 =14.0 and 12.5 mM). CBD and (+)-CBD were also active (IC 50 =22.0 and 17.0 mM). 5 CBD (IC 50 =27.5 mM), (+)-CBD (IC 50 =63.5 mM) and (7)-7-hydroxy-CBD (IC 50 =34 mM), but not the other analogues (IC 50 4100 mM), weakly inhibited [ 14 C]-AEA hydrolysis. 6 Only the (+)-isomers exhibited high a nity for CB 1 and/or CB 2 cannabinoid receptors. 7 These ®ndings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological e ects of CBD and its analogues. In view of the facile high yield synthesis, and the weak a nity for CB 1 and CB 2 receptors, (7)-5'-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.

The psychoactive constituent in cannabis, Δ(9)-tetrahydrocannabinol (THC), was isolated in the mid-1960s, but the cannabinoid receptors, CB1 and CB2, and the major endogenous cannabinoids (anandamide and 2-arachidonoyl glycerol) were identified only 20 to 25 years later. The cannabinoid system affects both central nervous system (CNS) and peripheral processes. In this review, we have tried to summarize research--with an emphasis on recent publications--on the actions of the endocannabinoid system on anxiety, depression, neurogenesis, reward, cognition, learning, and memory. The effects are at times biphasic--lower doses causing effects opposite to those seen at high doses. Recently, numerous endocannabinoid-like compounds have been identified in the brain. Only a few have been investigated for their CNS activity, and future investigations on their action may throw light on a wide spectrum of brain functions.

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