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

Abstract

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.

Acute Effects of a Selective Cannabinoid-2 Receptor Agonist on Neuroinflammation in a Model of Traumatic Brain Injury

“…The CB 2 R agonist 0-1966 (0-1966A) is an analog of bicyclic resorcinols (dimethoxy-resorcinol-dimethylheptyl), a chemical compound structurally similar to cannabidiol, as described by Wiley and associates (2002). This particular analog demonstrated superior CB 2 R selectivity (225-fold) and a high binding affinity for the CB 2 R (Ki = 22.5 nM); it was also shown to have poor affinity for CB 1 R (Wiley et al, 2002). Three naïve mice that did not receive surgery or treatment were also included.…”

G protein-coupled receptors as therapeutic targets for multiple sclerosis

“…JWH-015, a cannabinoid with a relatively high selectivity for CB2, was reported to suppress microglial activation [99]. O-1966, a selective CB2 agonist [100], was found to significantly improve the motor function in the chronic EAE model, the remitting-relapsing model and the adoptive transfer model [101]. Administration of HU-308, with a selectivity of ~500× for CB2 vs CB1 [102], improved EAE symptoms and reduced spinal cord lesions and microglial activation [97].…”

Expedient Soxhlet extraction of resorcinolic lipids from wheat grains

“…However further studies of alkylresorcinols attributed to them a wide range of desired biological traits, such as antibacterial and antifungal activities mentioned above, and also antiparasitic, antitumor and antioxidant effects (Kozubek and Tyman, 1999). Resorcinolic lipids may be used, therefore, in the treatment of various pathological events, for example as longlasting hydrophobic anti-inflammatory drugs or analogues of cannabinoids (Barrero et al, 1993;Kozubek and Tyman, 1999;Wiley et al, 2002). This class of phenolic lipids is also important from an economical point of view.…”