Structure activity relationships of tetrahydrocannabinol analogues on human cannabinoid receptors

Gareau, Yves; Dufresne, Claude; Gallant, Michel; Rochette, C.; Sawyer, Nicole; Slipetz, Deborah; Tremblay, Nathalie; Weech, Philip K.; Metters, Kathleen M.; Labelle, Marc

doi:10.1016/0960-894x(95)00573-c

Cited by 103 publications

(89 citation statements)

References 18 publications

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“…The binding data for compounds that bind to CB 2 reported so far (24)(25)(26)(27)(28), as well as for HU-308 in the present paper, indicate that major differences exist between the structure-activity relationships (SAR) for binding to CB 1 and CB 2 . Although a free phenolic group in cannabinoid-type compounds is a basic structural feature for CB 1 binding and cannabimimetic activity (29), it is not required for CB 2 binding.…”

Section: Resultsmentioning

confidence: 90%

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HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

Hanŭs

Breuer

Tchilibon

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

528

367

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Two cannabinoid receptors have been identified: CB1, present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB2, present outside the CNS, in peripheral organs. There is evidence for the presence of CB2-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB2-specific agonist, code-named HU-308. This cannabinoid does not bind to CB1 (Ki > 10 M), but does so efficiently to CB2 (Ki ‫؍‬ 22.7 ؎ 3.9 nM); it inhibits forskolin-stimulated cyclic AMP production in CB2-transfected cells, but does so much less in CB1-transfected cells. HU-308 shows no activity in mice in a tetrad of behavioral tests, which together have been shown to be specific for tetrahydrocannabinol (THC)-type activity in the CNS mediated by CB1. However, HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity. The hypotension, the inhibition of defecation, the anti-inflammatory and peripheral analgesic effects produced by HU-308 are blocked (or partially blocked) by the CB2 antagonist SR-144528, but not by the CB1 antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension, inflammation, and pain.

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Section: Resultsmentioning

confidence: 90%

“…24). Most of these compounds exhibit only modest selectivity (25)(26)(27). Of particular relevance to the present work are cannabinoid-type compounds, such as L-758,656 and L-759,633, in which the phenolic group is blocked as a methyl ether.…”

Section: Resultsmentioning

confidence: 99%

HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

Hanŭs

Breuer

Tchilibon

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

528

367

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“…Several previous studies have explored the role of oxygen in CB 2 binding. Synthesis of a series of ⌬ 8 -THC analogs in which the phenolic hydroxyl at position 1 was removed (deoxy-⌬ 8 -THC analogs) or replaced with a methoxyl resulted in analogs with selectivity for CB 2 receptors (Gareau et al, 1996;Huffman et al, 1996Huffman et al, , 1999. Incorporation of an oxygen into a fourth ring attached at C1 also increased CB 2 selectivity, suggesting possible differences in the interaction of oxygen in the binding pockets of CB 1 and CB 2 receptors (Reggio et al, 1997).…”

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confidence: 99%

“…Methylation of the phenols of the resorcinols drastically decreased or eliminated CB 1 affinity, perhaps because hydrogen donation is less likely from a methoxy group than from the free hydroxyl group of ⌬ 9 -THC (B. R. Martin, unpublished observations). Similarly, methoxy substitution for the phenolic hydroxyl in the methyl esters of ⌬ 8 -and ⌬ 9(11) -THC-dimethylheptyl resulted in analogs that were CB 2 -selective and had little CB 1 affinity (Gareau et al, 1996;Huffman et al, 1999;Ross et al, 1999).…”

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confidence: 99%

Resorcinol Derivatives: A Novel Template for the Development of Cannabinoid CB₁/CB₂ and CB₂-Selective Agonists

Wiley

Beletskaya²,

Ng³

et al. 2002

J Pharmacol Exp Ther

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The role of the oxygen of the benzopyran substituent of ⌬ 9 -tetrahydrocannabinol in defining affinity for brain cannabinoid (CB 1 ) receptors is not well understood; however, it is known that opening the pyran ring can result in either increased potency and affinity, as in CP 55,940 [(Ϫ)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol], or in an inactive cannabinoid, as in cannabidiol. In the present study, a series of bicyclic resorcinols that resemble cannabidiol were synthesized and tested in vitro and in vivo. Analysis of the structure-activity relationships of these analogs revealed several structural features that were important for maintaining CB 1 receptor recognition and in vivo activity, including the presence of a branched lipophilic side chain and free phenols as well as substitution of a cyclohexane as the second ring of these bicyclic cannabinoids. Many of these analogs exhibited CB 2 selectivity, particularly the dimethoxyresorcinol analogs, and this selectivity was enhanced by longer side chain lengths. Hence, unlike cannabidiol, these resorcinol derivatives had good affinity for CB 1 and/or CB 2 receptors as well as potent in vivo activity. These results suggest that the resorcinol series represent a novel template for the development of CB 2 -selective cannabinoid agonists that have the potential to offer insights into similarities and differences between structural requirements for receptor recognition at CB 1 and CB 2 receptors.

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“…It has been demonstrated that compounds lacking the phenolic hydroxyl of the A ring or having it occupied in an ether linkage, show enhanced affinity for CB2 as well as selectivity. 167 The observations made with these modifications indicate the involvement of additional specific electronic and steric factors in ligand recognition at the CB2 receptor. It is also important to note that elimination of the B ring of the classical cannabinoid core with the biphenyl or triaryl core has resulted in compounds that are more CB2 selective also.…”

Section: Introductionmentioning

confidence: 97%

Synthesis of Novel Cannabinoid Ligands and Their Use as Anti-Glioma and Anti-Inflammatory Agents

Gurley¹

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Structure activity relationships of tetrahydrocannabinol analogues on human cannabinoid receptors

Cited by 103 publications

References 18 publications

HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

Resorcinol Derivatives: A Novel Template for the Development of Cannabinoid CB₁/CB₂ and CB₂-Selective Agonists

Synthesis of Novel Cannabinoid Ligands and Their Use as Anti-Glioma and Anti-Inflammatory Agents

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Structure activity relationships of tetrahydrocannabinol analogues on human cannabinoid receptors

Cited by 103 publications

References 18 publications

HU-308: A specific agonist for CB 2 , a peripheral cannabinoid receptor

HU-308: A specific agonist for CB 2 , a peripheral cannabinoid receptor

Resorcinol Derivatives: A Novel Template for the Development of Cannabinoid CB1/CB2 and CB2-Selective Agonists

Synthesis of Novel Cannabinoid Ligands and Their Use as Anti-Glioma and Anti-Inflammatory Agents

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HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

Resorcinol Derivatives: A Novel Template for the Development of Cannabinoid CB₁/CB₂ and CB₂-Selective Agonists