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NEUROPHARMACOLOGY

Pharmacological Characterization of Novel Water-Soluble Cannabinoids

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (B.R.M., J.L.W., I.B., L.J.S.-S., F.L.S., W.L.D.); Organon Laboratories, Ltd., Newhouse Industrial Estate, Lanarkshire, United Kingdom (J.C., J.A., J.B., D.H.); and Organix, Inc., Woburn, Massachusetts (B.S., J.Z., A.M., R.K.R.)

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.

Address correspondence to: Dr. Billy R. Martin, Department of Pharmacology and Toxicology, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613. E-mail: martinb{at}hsc.vcu.edu