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

R G Pertwee, T M Gibson, L A Stevenson, R A Ross, W K Banner, B Saha, R K Razdan, B R Martin

Research output: Contribution to journalArticle

43 Citations (Scopus)

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 languageEnglish
Pages (from-to)1577-1584
Number of pages8
JournalBritish Journal of Pharmacology
Volume129
Issue number8
DOIs
Publication statusPublished - 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

Pertwee, R. G., Gibson, T. M., Stevenson, L. A., Ross, R. A., Banner, W. K., Saha, B., ... Martin, B. R. (2000). O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties. British Journal of Pharmacology, 129(8), 1577-1584. https://doi.org/10.1038/sj.bjp.0703245

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 journalArticle

Pertwee, RG, Gibson, TM, Stevenson, LA, Ross, RA, Banner, WK, Saha, B, Razdan, RK & Martin, BR 2000, 'O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties', British Journal of Pharmacology, vol. 129, no. 8, pp. 1577-1584. https://doi.org/10.1038/sj.bjp.0703245
Pertwee, R G ; Gibson, T M ; Stevenson, L A ; Ross, R A ; Banner, W K ; Saha, B ; Razdan, R K ; Martin, B R . / O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties. In: British Journal of Pharmacology. 2000 ; Vol. 129, No. 8. pp. 1577-1584.
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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 -