Vol. 301, Issue 2, 679-689, May 2002

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

Jenny L. Wiley, Irina D. Beletskaya, Edward W. Ng, Zongmin Dai, Peter J. Crocker, Anu Mahadevan, Raj K. Razdan and Billy R. Martin

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (J.L.W., I.D.B., B.R.M.); and Organix, Inc., Woburn, Massachusetts (E.W.N., P.J.C., Z.D., A.M., R.K.R.)

The role of the oxygen of the benzopyran substituent of ⁹-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 CB₁ 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 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.