Cannabinoid Receptor Agonists with Selectivity for CBX or CB2 Receptors

Many established cannabinoids exhibit little difference in their affinities for CB1 and CB2 receptors (Table 1). These include delta-9-THC, CP 55,940 and anandamide. However, there are several recently developed compounds that do show significant selectivity for CB1 or CB2 receptors (Table 1). Apart from the antagonists, SRI41716A and LY320135 (Section 3.2.1), compounds with greater affinity for CB1 than CB2 receptors include three synthetic analogues of anandamide: methanandamide, O-585 and O-689 (Figure 5). All these compounds are agonists. Compounds with significantly greater affinity for CB2 than CB1 receptors include JWH-015, JWH-051 and the Merck Frosst compounds shown in Figure 9 (L-759,633 and L-759,656) and Figure 10. WIN 55,212-2 also exhibits modest selectivity for cannabinoid CB2 receptors. Although there are reports that JWH-015 and JWH-051 behave as CBj receptor agonists in vivo or in vitro (Huffman et al., 1996; Griffin et al., 1997), their activity in an established bioassay for CB2 receptor agonists has still to be reported. Also still to be announced are the pharmacological properties of the Merck Frosst compounds at both CB1 and CB2 receptors. Whilst CP 55,940 and WIN 55,212-2 are undoubtedly CB1, CB1(a) and CB2 receptor agonists (Rinaldi-Carmona et al., 1996a; Pertwee, 1997), there is uncertainty as to whether delta-9-THC and anandamide can activate CB2 receptors (Sections 5.1 and 6.2.2) although none that these ligands can serve as agonists for CB1 or CB1(a) receptors (Sections 5 and 6 and Rinaldi-Carmona et al., 1996a).

Even though potent, selective CB1 and CB2 receptor ligands have been developed, most binding data come from experiments that have been performed with radiolabelled probes having similar affinities for CB1 and CB2 receptors ([3H]CP 55,940, [3H]WIN 55,212-2 and the [3H]dimethylheptyl analogue of 11-hydroxy-hexahydrocannabinol) (Table 1; Devane et al., 1992a; Bayewitch et al., 1995). Some binding experiments have also been performed with the [3H]dimethylheptyl analogue of 11-hydroxy-delta-9-THC (see Pertwee, 1997). The relative affinity of this probe for CB1 and CB2 receptors has yet to be reported. It is worth noting, therefore, that its delta-8-THC analogue, HU-210, binds more or less equally well to CB1 and CB2 receptors (Table 1). The CB 1-selective ligand, [3H]SR 141716A, is now available, but relatively few binding experiments have been performed with this compound. No radiolabelled

Cb1 Cb2 Receptors
Figure 9 Structures of cannabinoid receptor ligands showing selectivity for cannabinoid CB2 receptors (see text and Table 1 for further details)
Figure 10 One of a series of indoles with high affinity and selectivity for CB2 receptors (see text, Table 1 and Gallant et al. (1996) for further details). It is listed in Table 1 as Compound 9

CB2-selective ligands have yet been produced. As to the question of whether ligands can be developed with significantly different affinities for CB1 and CB1W receptors, existing binding data indicate that the CB1 to CB1W receptor affinity ratio is 10.1 for SR141716A, 3-4 for delta-9-THC, CP 55,940 and WIN 55,212-2 and 0.83 for anandamide and that the rank order of affinity is CP 55,940>SR141716A>delta-9-THC>WIN 55,212-2>anandamide for CB1 receptors and CP 55,940>delta-9-THC>SR141716A>anandamide>WIN 55,212-2 for CB1(a) receptors (Rinaldi-Carmona et al., 1996a).


Although by far the highest concentrations of CB1 and CB1(a) mRNA are to be found in the CNS (Galiegue et al., 1995; Shire et al., 1995), it has been possible, largely by the application of reverse transcription coupled to the polymerase chain reaction, to demonstrate the presence of both these mRNAs in many peripheral tissues. Outside the CNS, the highest levels of human CB1 mRNA are in pituitary gland and immune cells, particularly B-cells and natural killer cells (Galiegue et al., 1995). As detailed by Pertwee (1997), other peripheral tissues of human, dog, rat and/or mouse that contain CB1 mRNA include immune tissues (tonsils, spleen, thymus, bone marrow), reproductive tissues (ovary, uterus, testis, vas deferens, prostate gland), gastrointestinal tissues (stomach, colon, bile duct), superior cervical ganglion, heart, lung, urinary bladder and adrenal gland. CB1(a) mRNA is thought to exist as a minor transcript, the ratio of CB1(a) to CB1 mRNA in humans never exceeding 0.2 and, in kidney, bile duct and certain areas of infant or 2-year old brain, diminishing to 0.02 or less (Shire et al., 1995, and Section 4.3).

CB2 mRNA occurs mainly in immune tissues, for example human, rat and mouse spleen, human leukocytes (B cells>T cells), human tonsils and rat peritoneal mast cells (Das et al., 1995; Facci et al., 1995; Galiegue et al., 1995). Levels of human CB2 mRNA are particularly high in B-cells, natural killer cells and spleen as well as in tonsils, where they are similar to those of human CB1 mRNA in cerebellum (Galiegue et al., 1995). CB2 mRNA has also been detected, albeit at lower concentrations, in human thymus gland, bone marrow, pancreas and lung. Its levels in peripheral tissues greatly exceed those of CB1 mRNA (Galiegue et al., 1995). Although CB2 mRNA has not been detected in human or rat brain (Munro et al., 1993; Galiegue et al., 1995), there is one report of its presence together with CB1 mRNA in cultures of mouse cerebellar granule neurones (Skaper et al., 1996).

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