Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1577-1584 |
| Number of pages | 8 |
| Journal | British Journal of Pharmacology |
| Volume | 129 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Apr 2000 |
Keywords
- cannabinoids
- cannabinoid CB1 receptors
- cannabinoid CB2 receptors
- 3-(5 '-cyano-1 ',1 '-dimethylpentyl)-1-(4-N
- morpholinobutyryloxy)-Delta(8)-tetrahydrocannabinol hydrochloride
- O-1057
- mouse tail flick test
- body temperature
- spontaneous activity
- mouse vas deferens
- MOUSE VAS-DEFERENS
- MYENTERIC PLEXUS
- CROSS-TOLERANCE
- SR141716A
- WIN-55,212-2
- PHARMACOLOGY
- INHIBITION
- ANTAGONIST
- MORPHINE
Cite this
O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties. / Pertwee, R G ; Gibson, T M ; Stevenson, L A ; Ross, R A ; Banner, W K ; Saha, B ; Razdan, R K ; Martin, B R .
In: British Journal of Pharmacology, Vol. 129, No. 8, 04.2000, p. 1577-1584.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties
AU - Pertwee, R G
AU - Gibson, T M
AU - Stevenson, L A
AU - Ross, R A
AU - Banner, W K
AU - Saha, B
AU - Razdan, R K
AU - Martin, B R
PY - 2000/4
Y1 - 2000/4
N2 - 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.
AB - 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.
KW - cannabinoids
KW - cannabinoid CB1 receptors
KW - cannabinoid CB2 receptors
KW - 3-(5 '-cyano-1 ',1 '-dimethylpentyl)-1-(4-N
KW - morpholinobutyryloxy)-Delta(8)-tetrahydrocannabinol hydrochloride
KW - O-1057
KW - mouse tail flick test
KW - body temperature
KW - spontaneous activity
KW - mouse vas deferens
KW - MOUSE VAS-DEFERENS
KW - MYENTERIC PLEXUS
KW - CROSS-TOLERANCE
KW - SR141716A
KW - WIN-55,212-2
KW - PHARMACOLOGY
KW - INHIBITION
KW - ANTAGONIST
KW - MORPHINE
U2 - 10.1038/sj.bjp.0703245
DO - 10.1038/sj.bjp.0703245
M3 - Article
VL - 129
SP - 1577
EP - 1584
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 8
ER -