Bicyclic cannabinoids

The benzopyran ring is not essential for activity. The pyran oxygen can be substituted by nitrogen or can be eliminated in open-ring mono- or bisphenolic compounds. The recently developed CB2-selective ligand HU-308 (5) is an example of such a bicyclic cannabinoid (Hanus et al., 1999). 

There are two major groups of synthetic compounds which have cannabin-oid activity, but which differ chemically from the tricyclic THC-like canna-binoids the bicyclic cannabinoids, exemplified by compound CP55940 (23), and the (aminoalkyl)indoles exemplified by pravadoline (24a). A detailed SAR analysis of these groups of compounds is beyond the scope of this review. The bicyclic cannabinoids and derivatives have been reviewed previously [105] recent publications deal mainly with related tricyclic non-classical cannabinoids [106] and with the (aminoalkyl)indoles [92, 107]. It is of interest to note that while the bicyclic cannabinoids were originally prepared as simplified cannabinoids, the cannabinoid-type activity of the (ami-noalkyl)indoles was discovered by serendipity. These compounds were synthesized in a project aimed at the discovery of novel nonsteroidal anti-inflammatory agents presumably based on the indomethacin structure. However, while they did not possess anti-inflammatory properties, they were found to be antinociceptive, and to inhibit the electrically evoked contractions in a mouse vas deferens muscle preparation. This led to binding experi-... 

Melvin LS, Johnson MR (1987) Structure-activity relationships of tricyclic and nonclassical bicyclic cannabinoids. NIDA Res Monogr 79 31-47... 

Melvin LS, Milne GM, Johnson MR, Subramaniam B, Wilken GH, Howlett AC (1993) Structure-activity relationships for cannabinoid receptor-binding and analgesic activity studies of bicyclic cannabinoid analogs. Mol Pharmacol 44 1008-1015... 

The recently introduced ligand HU-308 (28, Fig. 7), which has the opposite absolute configuration from all other CC and NCC analogs, is another example of bicyclic cannabinoid receptor ligands (Hanus et al. 1999) and exhibits a high degree of CB2 selectivity. 

Compton DR, Johnson MR, Melvin LS, Martin BR (1992b) Pharmacological profile of a series of bicyclic cannabinoid analogs classification as cannabimimetic agents. J Pharmacol Exp Ther 260 201-209... 

Melvin, L. S., Milne, G. M., Johnson, M. R., Subramaniam, B., WUken, G. H., and Howlett, A. C. (1993) Sttucture-activity relationships for cannabinoid receptorbinding and analgesic activity studies of bicyclic cannabinoid analogs. Mol. Pharmacol. 44, 1008-1015. 

The term non-classical cannabinoids is applied to a group of bicyclic compounds identified by researchers at Pfizer in the 1980s [129], These compounds lack the pyran ring of the classical cannabinoids and the second phenolic hydroxyl group of the cannabidiols, resulting in a simplified substructure represented by CP 47,497 (192) [130, 131], The non-classical cannabinoids still retain the three main pharmacophoric elements described above for the classical cannabinoids and the SAR in these regions parallels that of the classical cannabinoids [132]. 

The first identified cannabinoid receptor subtype, CB was cloned and demonstrated to have an amino acid sequence consistent with a tertiary structure typical of the seven transmembrane-spanning proteins that are coupled to G proteins. In addition to being found in the central nervous system, mRNA for CB has also been identified in testes. The central nervous system responses to cannabinoid compounds are believed to be mediated exclusively by CB, inasmuch as CB2 transcripts could not be found in brain tissue by either Northern analysis or in situ hybridization studies. CBj transduces signals in response to central-nervous-system-active constituents of C. sativa as well as synthetic bicyclic and tricyclic cannabinoid analogs, aminoalkylindole, and eicosanoid cannabimimetic compounds. CB is coupled to G, to inhibit adenylate cyclase activity and to a pertussis-sensitive G protein to regulate Ca2+ currents. 

Bicyclic and tricyclic cannabinoids, (IV), prepared by Makriyannis (5) were effective as both CBj and CB2 agonists/antagonists and used as an effective and safe treatment option in pain management. Dibenzo[b,d]pyran derivatives, (V), effective as selective CB2 receptor agonists (V) also prepared by Makriyannis (6) were effective in treating... 

Nonclassical cannabinoids consist of bicyclic and tricyclic analogues of A -THC that lack a pyran ring examples include CP55940, CP47497, CP55244 and HU-308 (Fig. 6). They are, therefore, closely related to the classical cannabinoids. 

Berglund BA, Fleming PR, Rice KC, Shim JY, Welsh WJ, Howlett AC (2000) Development of a novel class of monocyclic and bicyclic alkyl amides that exhibit CBI and CB2 cannabinoid receptor affinity and receptor activation. Drug Des Discov 16 281-294... 

The cannabinoid ligand can be classified according to Ooms et al [43] into six groups i) classical, ii) nonclassical, iii) bicyclic, iv) aminoalkylindoles, v) endocannabinoid analogues, vi) diarylpyrazoles. Ooms et al [43] studied the pharmacophore of 3-alkyl-5-arylimidazolidinediones as a new CBi cannabinoid receptor. Thomas et al [44] have studied SAR data on a series of 1,5-diphenylpyrazoles proposing a pharmacophoric alignment of these compounds with THC... 

The potent bicyclic synthetic cannabinoid PH]CP55,940 has been used to demonstrate the presence of CBRs in brain and peripheral organs (Devane et al., 1988 Herkenham et al., 1990 Gerard et al., 1991 Matsuda, 1997). We showed that specific binding of PH]CP55,940 to live sea urchin sperm is saturable 5.16 1.02 tiM Hill coefficient 0.98 0.004 B, 2.22 0.42 pmoles/mg protein... 

A series of novel bicyclic triazolopyridazine cannabinoid receptor-1 (CB1) antagonists is described. We previously reported a series of di-aryl pyrazine carboxamide CB1 antagonists, and the progression of this series to include fused bicyclic triazolopyridazine CB1 antagonists is reported herein. The bicyclic series leads to compounds with greater in vitro potency and selectivity (CB1/CB2) as compared to the monocyclic series. In vitro and in vivo profiling of the triazolopyridazine CB1 antagonists is described. 

From a previous medicinal chemistry campaign, novel substituted benzene sulfonamides were identified as selective cannabinoid CB2 receptor ligands. In order to improve upon the selectivity of these compounds, the central benzene template was modified to accommodate a more lipophilic bicyclic system. The synthesis, SAR and in vivo efficacy of this novel series of CB2 ligands will be presented. 

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