Classification of Cannabinoid Receptor Ligands

Classical Cannabinoids

Classical cannabinoids (CCs) are ABC-tricyclic terpenoid compounds bearing a benzopyran moiety (Figs. 1-3,5, and 6). This class includes the natural product (-)-49-THC (1, Fig. 1), the more stable and almost equipotent isomer (-)-48-THC (2, Fig. 1), and other pharmacologically active constituents of the plant Cannabis sativa. Many CC analogs have been synthesized and evaluated pharmacologically and biochemically (for reviews see Goutopoulos and Makriyannis 2002; Khanolkar et al. 2000; Makriyannis and Goutopoulos 2004; Makriyannis and Rapaka 1990; Mechoulam et al. 1999; Palmer et al. 2002; Razdan 1986). SAR studies recognize four pharmacophores within the cannabinoid prototype: a phenolic hydroxyl (PH), a lipophilic alkyl side chain (SC), a northern aliphatic hydroxyl (NAH), and a southern aliphatic hydroxyl (SAH). The first two are encompassed in the plant-derived cannabinoids, while all four pharmacophores are represented in some of the synthetic NCCs developed by Pfizer (e.g., 25, Fig. 7). The CC structural features that are important for cannabinoid activity are discussed below.

SAR of Classical Cannabinoids

The Phenolic Hydroxyl This group can be substituted by an amino group, but not by a thiol group (Matsumoto et al. 1977a) while its replacement by a fluorine atom diminishes CBi affinity (e.g., 3, Fig. 2) (Martin et al. 2002). It has also been shown that CCs in which the phenolic hydroxyl is either replaced by a methoxy group (e.g., 4, Fig. 2) or totally absent (5 and 6, Fig. 2) retain some receptor-binding affinity, especially for CB2 (Gareau et al. 1996; Huffman et al. 2002, 1999, 1996). However, this is not the case for the cannabinol series in which the C-ring is fully aromatized (Khanolkar et al. 2000; Mahadevan et al. 2000).

The Benzopyran Ring This ring is not essential for activity and its expansion to B-ring homocannabinoid derivatives has been considered since the early days of

Cannabinoide Ring Ring
Fig. 1. The structures of (-)-49-and (-^^-tetrahydrocannabinol (THC)
Cannabinoid Ligand
Fig. 2. Phenolic hydroxy!, B- and C-ring modified cannabinoid analogs

cannabinoid structure-activity correlations (Matsumoto et al. 1977b). The pyran oxygen can be substituted by nitrogen as exemplified by compound 7 developed at Pfizer (Fig. 2) (Melvin et al. 1995) or can be eliminated in open phenol or resorcinol analogs. The latter gave rise to the NCC class described in Sect. 2.2.

Neither the double bond nor the 9-methyl at the C-ring is necessary for activity, and this ring maybe modified into a heterocyclic system (e.g., 8, Fig. 2) (Lee et al. 1977,1983; Osgood et al. 1978; Pars et al. 1976).

C-3 Side Chain This alkyl chain has been recognized as the most critical CC pharmacophore group. Variation of the rc-pentyl group of natural cannabinoids can lead to wide variations in potency and selectivity. Optimal activity is obtained with a seven or eight carbon length substituted with 1',1'-or 1',2'-dimethyl groups (e.g., 9, Fig. 3) as was first demonstrated by Adams (Adams et al. 1949; Huffman et al. 2003b; Liddle and Huffman 2001). More recent studies have focused on novel side chains bearing 1',1'-cyclic moieties (Papahatjis et al. 1998,2001,2002,2003). Some of the synthesized analogs exhibited remarkably high affinities for both CB1 and CB2 cannabinoid receptors (e.g., 10,11,12, Fig. 3) while in vitro pharmacological testing found the dithiolane analog 10 to be a potent CBi-selective agonist (Papahatjis et al. 2003). The results of these studies suggest the presence of a subsite within the CB1 and CB2 binding domain at the level of the benzylic side carbon in the THC series. In an effort to define the stereochemical limits of this putative subsite, we generated receptor-essential volume maps and receptor-excluded volume maps using molecular modeling approaches (Fig. 4) (Papahatjis et al. 2003).

The observation that the bulky adamantyl 48-THC (13, Fig. 3) (Khanolkar et al. 2000; Palmer et al. 2002) exhibits considerable affinity and selectivity for CB1 points to a greater tolerance for steric bulk in that receptor subsite. Oxygen atoms (ethers) and unsaturations (Busch-Petersen et al. 1996; Papahatjis et al. 1998)

Fig. 3. Representative C-1' side chain-modified analogs

Fig. 4. Molecular modeling of (-)-48-THC ligands with different substitution in the C-1' side chain position using molecular mechanics/molecular dynamics. CB1/CB2 receptor-excluded volume map (redcontours)and essential volume map (white grid) for the C-1' subsite in 48-THC series. The red area represents the free space within the receptor region that accommodates high-affinity C-1'-substituted ligands, whereas, C-1' substituents falling within the white grid experience unfavorable or less favorable interactions at the binding site

Papahatjis
Fig. 5. Representative side chain-modified analogs

within the chain or terminal carboxamido, cyano, azido, and halogen groups are also well tolerated (Charalambous et al. 1991; Crocker et al. 1999; Khanolkar et al. 2000; Martin et al. 1993, 2002; Nikas et al. 2004; Tius et al. 1997, 1993) (e.g., 14, Fig. 3; 15,16,17, Fig. 5). The side chain seems to be the place of choice for halogen substitution and a considerable enhancement in affinity for CB1 is observed by halogen substitution at the end carbon of the side chain with the bulkier halogens producing the largest effects (e.g., 18, Fig. 5). Additionally, naphthyl, phenyl, and cycloalkyl groups have served as side chain substituents (Krishnamurthy et al. 2003; Nadipuram et al. 2003; Papahatjis et al. 1996). Thus, substitution of the 1',1'-dimethylalkyl side chain with a 1',1'-dimethylcycloalkyl or 1',1'-dimethylphenyl group can lead to analogs possessing high affinities for both CBi and CB2 (e.g., 19, Fig. 5). In another variation, novel tetracyclic analogs of 48-THC in which the alkyl side chain is conformationally more defined by adding a fourth ring in the ABC-tricyclic cannabinoid skeleton fused to the aromatic A-ring have also been reported (e.g., 20, Fig. 5) (Khanolkar et al. 1999).

Northern Aliphatic Hydroxyl Group It has been shown that introduction of a hy-droxyl group at the C-9 or C-11 positions (northern aliphatic hydroxyl; NAH) leads to significant enhancement in affinity and potency for CB1 and CB2. Thus, (-)-11-hydroxydimethylheptyM8-THC (21, Fig. 6), a ligand that has received considerable attention because of its high affinity for both receptors, is more potent than the parent analog with no 11-hydroxy substitution (Mechoulam et al. 1988, 1987). This is also the case for the cannabinol series in which the C-ring is fully aromatized (Rhee et al. 1997) and in the hexahydrocannabinols (HHC, e.g., 22 and 23, Fig. 6) in which the C-ring is fully saturated. It has also been shown that the relative configuration of C-9 substituents in CCs can have significant effects in the compound's potency (Kriwacki and Makriyannis 1989; Reggio et al. 1989) where

Fig. 6. Cannabinoid analogs possessing a northern aliphatic hydroxyl (NAH) group

Fig. 6. Cannabinoid analogs possessing a northern aliphatic hydroxyl (NAH) group an unfavorable orientation of a C-9 hydroxyl or hydroxymethyl substituent can seriously interfere with this ligand's ability to interact with cannabinoid receptors. Based on the relative configuration at the C-9 position, the HHC encompasses two types of isomers (9a and 90). Although both isomers are biologically active, the ^-epimers in which the C-9 hydroxyl or hydroxymethyl group is equatorial (e.g., 22 and 23, Fig. 6) have been shown to be more potent than the a-axial isomers (Devane et al. 1992a; Wilson et al. 1976; Yan et al. 1994). The preference for the 9^ relative configuration has been used for the design and synthesis of high-affinity photoactivatable probes for the cannabinoid receptors (e.g., AM1708,70, Fig. 19) (Khanolkar et al. 2000). Presence of a C-9 carbonyl group encompassed in nabilone (24, Fig. 6) is also known to significantly enhance cannabinergic activity (Archer et al. 1986). Although the nature of the substituent at the northern end of the classical cannabinoid structure has an effect on the ligands' potencies, these effects have not yet been fully investigated. Thus, 9-nor-49-THC, a molecule that lacks a C-9 substituent, exhibits significant cannabinoid activity (Martin et al. 1975).

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