Cannabinoid Receptor Ligands

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Endogenous cannabinoid receptor ligands (endocannabinoids) such as anandamide and 2-arachidonoyl glycerol have been isolated20,70 and are able to bind and activate the cloned cannabinoid receptors. A common property of these endocannabinoids, sometimes referred to as eicosanoids, is that they are chemical derivatives of the polyunsaturated fatty acid, arachi-donic acid. They serve as neurotransmitters/neuromodulators, are not stored in vesicles but instead are synthesised on demand and released from neurones as a result of depolarisation and Ca+ influx.23,87 They activate presynaptic receptors and are then removed from the extracellular space by a membrane transport process and hydrolysed by the microsomal enzyme, fatty acid amide hydrolase, with anandamide being hydrolysed to arachidonic acid and ethanola-mine.

R(+)Methanandamide is a synthetic analogue of anandamide more resistant to hydrolysis than anandamide. Other synthetic cannabinoid receptor agonists can be categorised into 3 chemical drug groups. 1) Classical 2) Nonclassical and 3) aminoalkylindoles. Classical cannab-inoids include plant-derived compounds such as cannabinol and cannabidiol, and their synthetic analogues. The best known is A9THC, however other cannabinoids in this group include the synthetic analogue 11-hydroxy A8-dimethylheptyl (HU210). Nonclassical cannabinoids consist of bicyclic and tricyclic analogues of A9THC but lack the pyran ring; CP55,940 is perhaps the most widely used. The aminoalkylindoles are structurally different from the classical and nonclassical cannabinoids, resulting in binding differences. WIN55,212-2 is a member of this class of cannabinoids.

Receptor agonists differ in their affinities and efficacies for the cannabinoid receptors.85 A9THC binds equally to CB1 and CB2 in the nanomolar range, acting as a partial agonist for the CB1 receptor, similar to anandamide. Cannabinol and cannabidiol have lower affinities and efficacy for CB1 receptors than A9THC. In contrast, HU210, WIN55,212-2 and CP55,940 have greater affinities for the CB1 receptor. For WIN 55,212-2, an inactive isomer, WIN55,212-3, exists which can serve as a convenient control.

Several cannabinoid receptor antagonists have also been synthesised, e.g., SR141716A is a well-studied and extremely potent CB1 selective antagonist (see refs. 85 and 86 for review). SR141716A is able to reverse or prevent the CB1 receptor agonist-mediated effects in vivo and in vitro.6,9,59,84,101 If administered alone at high doses it may behave like an inverse agonist, producing responses opposite to CB1 agonists.57,92 SR141716A appears to be more potent against noneicosanoid cannabinoid agonists. Structural analogues including AM281 and AM251 have been developed, with AM281 being slightly less potent than SR141716A. Similar to

SR141716A, AM281 attenuates the effects of cannabinoid receptor agonists and when administered alone can behave like an inverse agonist.30

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