Abstract
The role of the oxygen of the benzopyran substituent of Δ9-tetrahydrocannabinol in defining affinity for brain cannabinoid (CB1) 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 [(−)-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 CB1receptor 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 CB2 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 CB1 and/or CB2 receptors as well as potent in vivo activity. These results suggest that the resorcinol series represent a novel template for the development of CB2-selective cannabinoid agonists that have the potential to offer insights into similarities and differences between structural requirements for receptor recognition at CB1 and CB2 receptors.
Footnotes
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Research supported by National Institute on Drug Abuse Research Grants DA-03672 and DA-05488 and Training Grant DA-07027.
- Abbreviations:
- THC
- tetrahydrocannabinol
- CP 55,940
- (−)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol
- MPE
- maximal possible antinociceptive effect
- CB1
- brain cannabinoid
- THF
- tetrahydrofuran
- TLC
- thin layer chromatography
- DMH
- dimethylheptyl
- DM
- dimethyl
- Received October 15, 2001.
- Accepted January 22, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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