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

1 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)-Delta(8)-tetrahydrocannabinol hydrochloride (O-1057), would interact with cannabinoid receptors when water or saline were used as the only vehicle.

2 O-1057 displaced [H-3]-CP55940 from specific binding sites on Chinese hamster ovary (CHO) cell membranes expressing CB1 or CB2 cannabinoid receptors, with pK(i) values of 8.36 and 7.95 respectively. It also displaced [H-3]-CP55940 from specific binding sites on rat brain membranes (pK(i) = 7.86).

3 O-1057 inhibited forskolin-stimulated cyclic AMP production by both CB1- and CB2-transfected CHO cells (pEC(50) = 9.16 and 9.72 respectively), its potency matching that of CP55940 and exceeding that of Delta(9)-tetrahydrocannabinol.

4 In the mouse isolated vas deferens, O-1057 inhibited electrically-evoked contractions with pEC(50) and E-max values of 9.73 and 76.84% respectively. It was antagonized by 100 nM SR141716A, the pK(B) of SR141716A against O-1057 (8.90) approximating to that against CP55940 (8.97).

5 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 Delta(9)-tetrahydrocannabinol and, at 0.1 mg kg(-1) i.v., was antagonized by SR141716A (3 mg kg(-1) i.v.).

6 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.