Comparison of novel cannabinoid partial agonists and SR141716A in the guinea-pig small intestine

A A Coutts, N Brewster, T Ingram, R K Razdan, R G Pertwee

Research output: Contribution to journalArticle

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Abstract

1 The controversial nature of the CB1 receptor antagonist, SR141716A, in the guinea-pig small intestine was investigated by comparing it with four analogues of Delta(8)-tetrahydrocannabinol (Delta(8)- THC): O-1184, O-1238, O-584 and O-1315.

2 These compounds (10-1000 nM) inhibited the electrically-evoked contractions with a rank order of potency of O-1235 > O-1184 > O-584 > O-1315. Log concentration-response curves for O-1238, O-1184 and O-1315 were significantly shifted to the right by SR141716A and the maxima were significantly less than that of the CB1 agonist, WIN55212-2, an indication of partial agonism.

3 Partial saturation of the triple bond in O-1184 to a cis double bond (O-1238) increased its potency as an agonist (pEC(50) from 6.42 to 7.63) and as an antagonist of WIN55212-2, (pK(B), from 8.36 to 9.49). Substitution of the terminal azide group by an ethyl group (O-584) or removal of the phenolic hydroxyl group (O-1315) had no significant effect on the agonist or antagonist potency. None of these analogues increased the twitch response in a manner resembling that of SR141716A.

4 O-1184 (10 and 100 nM) shifted the log concentration-response curve of WIN55212-2 for inhibition of the twitch responses to the right with pK(B) values of 8.29 and 8.38, respectively.

5 We conclude that these Delta(8)-THC analogues behave as partial agonists rather than silent antagonists at CB1 binding sites in this tissue. There was no evidence of antagonism of endocannabinoids thus supporting the hypothesis that, in this tissue, SR141716A is an inverse agonist of constitutively active CB1 receptors.

Original languageEnglish
Pages (from-to)645-652
Number of pages8
JournalBritish Journal of Pharmacology
Volume129
Publication statusPublished - 2000

Keywords

  • cannabinoid receptors
  • myenteric plexus
  • guinea-pig small intestine
  • 6 '-azidohex-2 '-yne-Delta 8-tetrahydrocannabinol
  • O-1184
  • SR141716A
  • cannabinoid receptor antagonists
  • ACETYLCHOLINE-RELEASE
  • SR 141716A
  • RECEPTOR ANTAGONIST
  • MYENTERIC PLEXUS
  • INVERSE AGONIST
  • CB1 RECEPTORS
  • MODULATION
  • MUSCLE
  • BINDS
  • MICE

Cite this

Comparison of novel cannabinoid partial agonists and SR141716A in the guinea-pig small intestine. / Coutts, A A ; Brewster, N ; Ingram, T ; Razdan, R K ; Pertwee, R G .

In: British Journal of Pharmacology, Vol. 129, 2000, p. 645-652.

Research output: Contribution to journalArticle

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T1 - Comparison of novel cannabinoid partial agonists and SR141716A in the guinea-pig small intestine

AU - Coutts, A A

AU - Brewster, N

AU - Ingram, T

AU - Razdan, R K

AU - Pertwee, R G

PY - 2000

Y1 - 2000

N2 - 1 The controversial nature of the CB1 receptor antagonist, SR141716A, in the guinea-pig small intestine was investigated by comparing it with four analogues of Delta(8)-tetrahydrocannabinol (Delta(8)- THC): O-1184, O-1238, O-584 and O-1315.2 These compounds (10-1000 nM) inhibited the electrically-evoked contractions with a rank order of potency of O-1235 > O-1184 > O-584 > O-1315. Log concentration-response curves for O-1238, O-1184 and O-1315 were significantly shifted to the right by SR141716A and the maxima were significantly less than that of the CB1 agonist, WIN55212-2, an indication of partial agonism.3 Partial saturation of the triple bond in O-1184 to a cis double bond (O-1238) increased its potency as an agonist (pEC(50) from 6.42 to 7.63) and as an antagonist of WIN55212-2, (pK(B), from 8.36 to 9.49). Substitution of the terminal azide group by an ethyl group (O-584) or removal of the phenolic hydroxyl group (O-1315) had no significant effect on the agonist or antagonist potency. None of these analogues increased the twitch response in a manner resembling that of SR141716A.4 O-1184 (10 and 100 nM) shifted the log concentration-response curve of WIN55212-2 for inhibition of the twitch responses to the right with pK(B) values of 8.29 and 8.38, respectively.5 We conclude that these Delta(8)-THC analogues behave as partial agonists rather than silent antagonists at CB1 binding sites in this tissue. There was no evidence of antagonism of endocannabinoids thus supporting the hypothesis that, in this tissue, SR141716A is an inverse agonist of constitutively active CB1 receptors.

AB - 1 The controversial nature of the CB1 receptor antagonist, SR141716A, in the guinea-pig small intestine was investigated by comparing it with four analogues of Delta(8)-tetrahydrocannabinol (Delta(8)- THC): O-1184, O-1238, O-584 and O-1315.2 These compounds (10-1000 nM) inhibited the electrically-evoked contractions with a rank order of potency of O-1235 > O-1184 > O-584 > O-1315. Log concentration-response curves for O-1238, O-1184 and O-1315 were significantly shifted to the right by SR141716A and the maxima were significantly less than that of the CB1 agonist, WIN55212-2, an indication of partial agonism.3 Partial saturation of the triple bond in O-1184 to a cis double bond (O-1238) increased its potency as an agonist (pEC(50) from 6.42 to 7.63) and as an antagonist of WIN55212-2, (pK(B), from 8.36 to 9.49). Substitution of the terminal azide group by an ethyl group (O-584) or removal of the phenolic hydroxyl group (O-1315) had no significant effect on the agonist or antagonist potency. None of these analogues increased the twitch response in a manner resembling that of SR141716A.4 O-1184 (10 and 100 nM) shifted the log concentration-response curve of WIN55212-2 for inhibition of the twitch responses to the right with pK(B) values of 8.29 and 8.38, respectively.5 We conclude that these Delta(8)-THC analogues behave as partial agonists rather than silent antagonists at CB1 binding sites in this tissue. There was no evidence of antagonism of endocannabinoids thus supporting the hypothesis that, in this tissue, SR141716A is an inverse agonist of constitutively active CB1 receptors.

KW - cannabinoid receptors

KW - myenteric plexus

KW - guinea-pig small intestine

KW - 6 '-azidohex-2 '-yne-Delta 8-tetrahydrocannabinol

KW - O-1184

KW - SR141716A

KW - cannabinoid receptor antagonists

KW - ACETYLCHOLINE-RELEASE

KW - SR 141716A

KW - RECEPTOR ANTAGONIST

KW - MYENTERIC PLEXUS

KW - INVERSE AGONIST

KW - CB1 RECEPTORS

KW - MODULATION

KW - MUSCLE

KW - BINDS

KW - MICE

M3 - Article

VL - 129

SP - 645

EP - 652

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

ER -