2-AG (2) was first isolated in 1995 from canine gut [14] and rat brains [15] and shown to be an endogenous CB ligand [14]. (2) is present in the rat brain in amounts 170-1,000 times greater than AEA [15, 168] and has been shown to be a potent full agonist at both the CB1 and CB2 receptors (CB1: Ki = 472 nM and CB2: Ki = 1,400 nM) [14, 169]. In addition, this endocannabinoid has typical cannabinoid-like activities including decreased spontaneous motor activity, immobility and production of hypothermia and analgesia [14]. The FAAH enzyme has been reported to hydrolyse (2) four times faster than its hydrolysis of AEA [170]. In addition, it has been proposed that the major enzymatic hydrolysis pathway of (2) occurs via the monoacylglycerol lipase rather than FAAH [171, 172].

Compound (2) has been reported to induce a rapid transient increase of intracellular free Ca2 + concentration in NG108-15 and HL-60 cells through a cannabinoid receptor-dependent mechanism [173, 174]. Furthermore, the Ca2 + increase in HL-60 cells appeared to be CB2 mediated as the effect could be blocked with a CB2 antagonist but not a CB1 antagonist [174]. Very little work has been carried out on the SAR of this endocannabinoid. In general, for the CB1 receptor, arachidonic acid was found to be the preferred fatty acid moiety, although some partially saturated structures had almost comparable activities [173]. It appears that the presence of a double bond at the Deposition is crucial for activity. With respect to the head group, the 2-glycerol isomer is preferable over both the 1- and 3-analogues. The ester moiety can be replaced by a ketone but agonistic activity in NG108-15 cells drops approximately 100-fold [175]. With regard to the CB2 receptor, much of the SAR overlaps with the results obtained for the CB1 receptor with the exception that glycerol esters of C22 fatty acids do not show appreciable activity in the CB1 assay, but do show appreciable activity in the CB2 assay [173].

Noladin ether

Noladin ether (3) was recently isolated from porcine brain [16] and found to bind to the CB1 receptor (Ki — 21.2nM), to bind weakly to the CB2 receptor (K >3 mM) and it causes typical cannabinoid-like effects such as sedation, hypothermia, intestinal immobility and mild antinociception in mice [16]. This endocannabinoid had previously been synthesised independently by both Mechoulam and co-workers [176] and Sugiura et al. [173]. SAR studies of this endocannabinoid are lacking in the literature, however, a recent publication highlighted the importance of the tetra-unsaturated C20 chain for high affinity at the CB1 receptor, increased saturation or replacement of the double bonds (with, for example, a cyclopropyl) had a detrimental effect on binding affinity [177].

The discovery and cloning of the CB1 and CB2 receptors has opened the way for the pharmaceutical industry to identify cannabinoid agonists with completely new templates. However, the first novel class of cannabinoid agonists (i.e. those not derived from THC) was discovered accidentally by the Sterling-Winthrop Research Group while studying conformationally restrained analogues of pravadoline (248) [178]. These pravadoline analogues displayed reduced ability to behave as non-steroidal anti-inflammatory agents that inhibit cyclooxygenase but increased ability to bind to the CB1 receptor.

In this initial study they found that the 4-methoxyphenyl ring could be replaced by a number of other aromatic rings, in particular, the 1-naphthyl ring was found to impart good potency. In addition, small substituents in the indole 2-position were favoured and importantly that potency resided in only one enantiomer of the aminoalkyl indole (AAI) (see Table 6.21). One compound of particular importance synthesised at this time is WIN 55,212-2 (254a), a potent agonist at both the CB1 and CB2 receptors. Although this compound was not developed as a drug, it has been widely used as a pharmacological tool in cannabinoid research. The Sterling-Winthrop research group [179] went on to carry out an extensive SAR study on unconstrained aminoalkyl indoles with over 100 analogues synthesised and tested, and

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