O‐1057, a potent water‐soluble cannabinoid receptor agonist with antinociceptive properties

Cannabinoids have low water solubility, necessitating the use of a solubilizing agent. In this paper we investigated whether a novel water‐soluble cannabinoid, 3‐(5′‐cyano‐1′,1′‐dimethylpentyl)‐1‐(4‐N‐morpholinobutyryloxy)‐Δ8‐tetrahydrocannabinol hydrochloride (O‐1057), would interact with cannabinoid receptors when water or saline were used as the only vehicle. O‐1057 displaced [3H]‐CP55940 from specific binding sites on Chinese hamster ovary (CHO) cell membranes expressing CB1 or CB2 cannabinoid receptors, with pKi values of 8.36 and 7.95 respectively. It also displaced [3H]‐CP55940 from specific binding sites on rat brain membranes (pKi=7.86). O‐1057 inhibited forskolin‐stimulated cyclic AMP production by both CB1‐ and CB2‐transfected CHO cells (pEC50=9.16 and 9.72 respectively), its potency matching that of CP55940 and exceeding that of Δ9‐tetrahydrocannabinol. In the mouse isolated vas deferens, O‐1057 inhibited electrically‐evoked contractions with pEC50 and Emax values of 9.73 and 76.84% respectively. It was antagonized by 100 nM SR141716A, the pKB of SR141716A against O‐1057 (8.90) approximating to that against CP55940 (8.97). O‐1057 also behaved as a CB1 receptor agonist in vivo, reducing mouse spontaneous activity and rectal temperature when injected intravenously and inducing antinociception in the mouse tail flick test when given intravenously (ED50=0.02 mg kg−1), intrathecally, intracerebroventricularly or by gavage. In all these assays, O‐1057 was more potent than Δ9‐tetrahydrocannabinol and, at 0.1 mg kg−1 i.v., was antagonized by SR141716A (3 mg kg−1 i.v.). These data demonstrate the ability of the water‐soluble cannabinoid, O‐1057, to act as a potent agonist at CB1 and CB2 receptors and warrant investigation of the clinical potential of O‐1057 as an analgesic. British Journal of Pharmacology (2000) 129, 1577–1584; doi:10.1038/sj.bjp.0703245