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

1 Cannabinoids have low water solubility, necessitating the use of a solubi lizing agent. In this paper we investigated whether a novel water-soluble c annabinoid, 3-(5'-cyano-1',1'-dimethylpentyl)-1-(4-N-morpholinobutyryloxy)- Delta(8)-tetrahydrocannabinol hydrochloride (O-1057), would interact with c annabinoid receptors when water or saline were used as the only vehicle. 2 O-1057 displaced [H-3]-CP55940 from specific binding sites on Chinese ham ster 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 p otency matching that of CP55940 and exceeding that of Delta(9)-tetrahydroca nnabinol. 4 In the mouse isolated vas deferens, O-1057 inhibited electrically-evolied 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 spo ntaneous activity and rectal temperature when injected intravenously and in ducing antinociception in the mouse tail flick test when given intravenousl y (ED50 = 0.02 mg kg(-1)), intrathecally, intracerebroventricularly or by g avage. In all these assays, O-1057 was more potent than Delta(9)-tetrahydro cannabinol and, at 0.1 mg kg(-1) i.v., was antagonized by SR141716A (3 mg k g(-1) i.v.). 6 These data demonstrate the ability of the water-soluble cannabinoid, O-10 57, to act as a potent agonist at CB1 and CB2 receptors and warrant investi gation of the clinical potential of O-1057 as an analgesic.