Cannabinoid affinity

Most relevant for the affinity for A9-THC and analogs to CB-receptors are the phenolic hydroxyl group at C-1, the kind of substitution at C-9, and the properties of the side chain at C-3. Relating to the structure-activity relationships (SAR) between cannabinoids and the CB-receptors, many different modified strucfures of fhis subsfance group were developed and fesfed. The most important variations include variations of the side chain at the olivetolic moiety of the molecules and different substitutions at positions C-11 and C-9. One of the most popular analogous compounds of A9-THC is HU-210 or (-)-trans-ll-OH-A8-THC-DMH, a cannabinoid with a F,l-dimethylheptyl side... 

In the search for new anti-inflammatory drugs structurally derived from indomethacine [147], Pravadoline showed psychotropic side effects in clinical trials. It became apparent that these effects are mediated through the cannabinoid receptor. Optimization of the structure Anally led to WIN-55,212-2 (8.6), which has a higher affinity to the CBl receptor than THC [148]... 

A -THC, the main psychoactive component of cannabis, is a moderately potent partial agonist of the CBi and CB2 receptors, while cannabidiol has little affinity for either receptor (Table 6.7). The term classical cannabinoids is used to describe cannabinoid receptor modulators structurally related to (67), which have a tricyclic dibenzopyran core. While several other structural types of cannabinoid receptor modulators have been discovered in recent years, the classical cannabinoids are still by far the most extensively studied group in terms of SAR and pharmacology. 

Tables 6.8-6.11 illustrate the wide range of C3 side-chain modified A -THC analogues that have been reported in the literature, together with associated in vitro and in vivo data. The affinity of classical cannabinoid analogues for the CBi receptor has been shown to correlate with depression of spontaneous activity and the production of antinociception, hypothermia and catalepsy in mice, and with psychomimetic activity in humans [93]. However, in some cases, there were unexplained differences between the observed trends in binding affinity and the trends in activity in mouse behavioural models. This may point to differences in efficacy among full agonists, partial agonists and antagonists/inverse agonists, or may reflect differences in in vivo metabolism or blood-brain barrier penetration or a combination of these factors.

A dithiolane group in the I -position has been shown to be at least as effective as the l, T-dimethyl group in enhancing the binding affinity of the classical cannabinoids, as can be seen by comparing compounds (123) and (124) with compounds (83) and (85). However, the constrained dithiolane compounds (125-127) showed decreased activity compared to their l, T-dimethyl analogues (99-101). In contrast to its l, T-dimethyl and ketone analogues, (117) and (119), the phenyl dithiolane compound (128) does not exhibit any CB2 selectivity. 

The CBi binding affinity of the hydroxymethyl and carboxyl analogues can be increased by substituting the C3 pentyl side chain for a dimethylheptyl side chain (Table 6.13). 1 l-Hydroxy-l, l -DMH A -THC, HU-210 (165), is an extremely potent cannabinoid agonist that has been widely used as a pharmacological tool [119]. Its ( + ) enantiomer, HU-211 (dexanabinol), which is in clinical development for the treatment of cognitive disorders, does not have high affinity for CBi receptors [120]. 

A fourth important pharmacophoric element was established for the non-classical cannabinoid series in the form of a southern aliphatic hydroxyl group. Addition of this group to (192) resulted in the high-affinity CBi and CB2 receptor full agonist CP 55,940 (193) [129, 133], the tritiated form of which was used to first demonstrate specific cannabinoid binding sites in brain tissue [134]. Its enantiomer, CP 56,667 (194) has lower affinity for the CBi receptor (Table 6.17). 

A number of protocols are available for measuring cannabinoid-binding affinity and as such there is a variation in reported K[ values for end-ocannabinoids across labs. For this reason, wherever possible, the relative affinity compared to AEA (measured in that protocol) will be given in an attempt to provide a benchmark for comparison. 

As outlined earlier, anandamide was the first among the endogenous cannabinoid receptor agonists to be identified. It exhibits higher binding affinity for the CBi receptor Ki — 89 nM) than for the CB2 receptor (il = 371 nM) [81]. Anandamide has typical cannabinoid activities including decreased spontaneous motor activity, immobility and production of hypothermia and analgesia [147, 148]. However, this action in vivo is of shorter duration than... 

In a study looking at oxygenated metabolites of AEA and their interaction with the cannabinoid system, a series of hydroxylated alkyl chains was prepared using different lipoxygenases as biocatalysts [152-154]. Of the seven AEA derivatives prepared, only the 5R-hydroxy (208), 125 -hydroxy (209) and 155 -hydroxy (210) derivatives had any affinity for the CBi receptor. Interestingly, the IdV-hydroxy compound (211) that was inactive at the CBi receptor displayed some affinity for the CB2 receptor [152] (see Table 6.18). 

Martin and co-workers [196] have also published on the discovery and SAR of pyrazole cannabinoids as described in the CBi agonist section. The analogues were tested for CBi receptor binding affinity and in a battery of in... 

Huffman JW, Yu S, Showalter Y, Abood ME, Wiley JL, Compton DR, Martin BR, Bramblett RD, Reggio PH. Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor. J Med Chem 1996 39 3875-3877. 

Nye JS, Voglmaier S, Martenson RE, Snyder SH. Myelin basic protein is an endogenous inhibitor of the high affinity cannabinoid binding site in brain. J Neurochem 1988 50 1170-1178. 

Yamada K, Rice KC, Flippen-Anderson JL, Eissenstat MA, Ward SJ, Johnson MR, Howlett AC. (Ami noalky Ijindole iso thiocyanates as potential electrophylic affinity ligands for the brain cannabinoid receptor. J Med Chem 1996 39 1967-1974. 

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