Received for publication April 19, 2006.
Revised June 2, 2006.
Accepted for publication June 2, 2006.

Pharmacological Characterization of Novel Water-soluble Cannabinoids

Abstract

Presently, there are numerous structural classes of cannabinoid receptor agonists, all of which require solubilization for experimental purposes because of their water-insolubility. 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 THC. 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.

Key words: cannabinoids, mice, pharmacokinetics, solubility, structure-activity relationship, tetrahydrocannabinol