TY - JOUR T1 - Pharmacological Characterization of Novel Water-Soluble Cannabinoids JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1230 LP - 1239 DO - 10.1124/jpet.106.104109 VL - 318 IS - 3 AU - Billy R. Martin AU - Jenny L. Wiley AU - Irina Beletskaya AU - Laura J. Sim-Selley AU - Forrest L. Smith AU - William L. Dewey AU - Jean Cottney AU - Julia Adams AU - James Baker AU - David Hill AU - Bijali Saha AU - John Zerkowski AU - Anu Mahadevan AU - Raj K. Razdan Y1 - 2006/09/01 UR - http://jpet.aspetjournals.org/content/318/3/1230.abstract N2 - Presently, there are numerous structural classes of cannabinoid receptor agonists, all of which require solubilization for experimental purposes. One strategy for solubilizing water-insoluble tetrahydrocannabinols is conversion of the phenolic hydroxyl to a morpholinobutyryloxy substituent. The hydrochloride salts of these analogs are water-soluble and active in vivo when administered in saline. The present investigation demonstrated that hydrochloride salts of numerous substituted butyryloxy esters are water-soluble and highly potent. The substitutions include piperidine, piperazine, and alkyl-substituted amino moieties. It was also discovered that incorporation of a nitrogenous moiety in the alkyl side chain increased the pharmacological potency of tetrahydrocannabinol. For example, an analog containing a pyrazole in the side chain (O-2545) was found to have high affinity and efficacy at cannabinoid 1 (CB1) and CB2 receptors, and when dissolved in saline, it was highly efficacious when administered either intravenously or intracerebroventricularly to mice. A series of carboxamido and carboxylic acid amide analogs exhibited high pharmacological potency, but their hydrochloride salts were not water-soluble. On the other hand, incorporation of imidazoles into the terminus of the side chain led to water-soluble hydrochloride salts that were highly potent when administered in saline to laboratory animals. It is now possible to conduct cannabinoid research with agonists that are water-soluble and thus obviating the need of solubilizing agents. The American Society for Pharmacology and Experimental Therapeutics ER -