Structural determinants of the partial agonist-inverse agonist properties of 6'-azidohex-2'-yne-¿8-tetrahydrocannabinol at cannabinoid receptors

R A Ross, T M Gibson, L A Stevenson, B Saha, P Crocker, R K Razdan, R G Pertwee

Research output: Contribution to journalArticle

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Abstract

1 We have extended previous investigations of four analogues of Delta(8)-tetrahydrocannabinol (Delta(8)-THC): 6'-azidohex-2'-yne-Delta(8)-THC (O-1184), 6'-azidohex-cis-2'-ene-Delta(8)-THC (O-1238) and octyl-2'-yne-Delta(8)-THC (O-584) and its I-deoxy-analogue (O-1315).

2 O-1184, O-1238 and O-584 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 8.28 to 8.45 (CBi) and 8.03 to 8.13 (CB2). The pK(i) values of O-1315 were significantly less, 7.63 (CB1) and 7.01 (CB2).

3 All the analogues inhibited forskolin-stimulated cyclic AMP production by CB1-transfected CHO cells(pEC(50) = 9.16 to 9.72). Only O-1238 behaved as a full agonist in this cell line.

4 In mouse vasa deferentia, O-1238 inhibited electrically-evoked contractions (pEC(50) = 10.18 and E-max = 70.5%). Corresponding values for O-1184 were 9.08 and 21.1% respectively. At 1 nM, O-1184 produced surmountable antagonism of the cannabinoid receptor agonist, CP55940. However, at 0.1 nM, O-1184 did not attenuate CP55940-induced inhibition of cyclic AMP production by CB(1-)transfected CHO cells.

5 In CB2-transfected CHO cells, cyclic AMP production was inhibited by CP55940 (pEC(50) = 8.59), enhanced by O-1184 and O-584 (pEC(50) = 8.20 and 6.86 respectively) and not significantly affected by O-1238 or O-1315.

6 At 100 nM, O-1184 and O-1238 produced surmountable antagonism of CP55940 in CB2 cells, decreasing the pEC(50) of CP55940 from 8.61 to 7.42 (O-1184) or from 8.54 to 7.44 (O-1238).

7 These data support the hypothesis that increasing the degree of unsaturation of the aliphatic side-chain of Delta(8)-THC analogues has little effect on CB1 or CB2 receptor affinity but can reduce CB1 receptor efficacy and reverse the direction of responses elicited at CB2 receptors.

Original languageEnglish
Pages (from-to)735-743
Number of pages9
JournalBritish Journal of Pharmacology
Volume128
Issue number3
DOIs
Publication statusPublished - Oct 1999

Keywords

  • cannabinoids
  • cannabinoid CB1 receptors
  • cannabinoid CB2 receptors
  • inverse agonism
  • 6 '-azidohex-2 '-yne-Delta(8-)tetrahydrocannabinol
  • O-1184
  • mouse vas deferens
  • SMALL-INTESTINE
  • CB2 RECEPTORS
  • PHARMACOLOGY
  • ACTIVATION
  • INHIBITION
  • ANTAGONIST
  • BINDING
  • POTENT

Cite this

Structural determinants of the partial agonist-inverse agonist properties of 6'-azidohex-2'-yne-¿8-tetrahydrocannabinol at cannabinoid receptors. / Ross, R A ; Gibson, T M ; Stevenson, L A ; Saha, B ; Crocker, P ; Razdan, R K ; Pertwee, R G .

In: British Journal of Pharmacology, Vol. 128, No. 3, 10.1999, p. 735-743.

Research output: Contribution to journalArticle

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abstract = "1 We have extended previous investigations of four analogues of Delta(8)-tetrahydrocannabinol (Delta(8)-THC): 6'-azidohex-2'-yne-Delta(8)-THC (O-1184), 6'-azidohex-cis-2'-ene-Delta(8)-THC (O-1238) and octyl-2'-yne-Delta(8)-THC (O-584) and its I-deoxy-analogue (O-1315).2 O-1184, O-1238 and O-584 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 8.28 to 8.45 (CBi) and 8.03 to 8.13 (CB2). The pK(i) values of O-1315 were significantly less, 7.63 (CB1) and 7.01 (CB2).3 All the analogues inhibited forskolin-stimulated cyclic AMP production by CB1-transfected CHO cells(pEC(50) = 9.16 to 9.72). Only O-1238 behaved as a full agonist in this cell line.4 In mouse vasa deferentia, O-1238 inhibited electrically-evoked contractions (pEC(50) = 10.18 and E-max = 70.5{\%}). Corresponding values for O-1184 were 9.08 and 21.1{\%} respectively. At 1 nM, O-1184 produced surmountable antagonism of the cannabinoid receptor agonist, CP55940. However, at 0.1 nM, O-1184 did not attenuate CP55940-induced inhibition of cyclic AMP production by CB(1-)transfected CHO cells.5 In CB2-transfected CHO cells, cyclic AMP production was inhibited by CP55940 (pEC(50) = 8.59), enhanced by O-1184 and O-584 (pEC(50) = 8.20 and 6.86 respectively) and not significantly affected by O-1238 or O-1315.6 At 100 nM, O-1184 and O-1238 produced surmountable antagonism of CP55940 in CB2 cells, decreasing the pEC(50) of CP55940 from 8.61 to 7.42 (O-1184) or from 8.54 to 7.44 (O-1238).7 These data support the hypothesis that increasing the degree of unsaturation of the aliphatic side-chain of Delta(8)-THC analogues has little effect on CB1 or CB2 receptor affinity but can reduce CB1 receptor efficacy and reverse the direction of responses elicited at CB2 receptors.",
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TY - JOUR

T1 - Structural determinants of the partial agonist-inverse agonist properties of 6'-azidohex-2'-yne-¿8-tetrahydrocannabinol at cannabinoid receptors

AU - Ross, R A

AU - Gibson, T M

AU - Stevenson, L A

AU - Saha, B

AU - Crocker, P

AU - Razdan, R K

AU - Pertwee, R G

PY - 1999/10

Y1 - 1999/10

N2 - 1 We have extended previous investigations of four analogues of Delta(8)-tetrahydrocannabinol (Delta(8)-THC): 6'-azidohex-2'-yne-Delta(8)-THC (O-1184), 6'-azidohex-cis-2'-ene-Delta(8)-THC (O-1238) and octyl-2'-yne-Delta(8)-THC (O-584) and its I-deoxy-analogue (O-1315).2 O-1184, O-1238 and O-584 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 8.28 to 8.45 (CBi) and 8.03 to 8.13 (CB2). The pK(i) values of O-1315 were significantly less, 7.63 (CB1) and 7.01 (CB2).3 All the analogues inhibited forskolin-stimulated cyclic AMP production by CB1-transfected CHO cells(pEC(50) = 9.16 to 9.72). Only O-1238 behaved as a full agonist in this cell line.4 In mouse vasa deferentia, O-1238 inhibited electrically-evoked contractions (pEC(50) = 10.18 and E-max = 70.5%). Corresponding values for O-1184 were 9.08 and 21.1% respectively. At 1 nM, O-1184 produced surmountable antagonism of the cannabinoid receptor agonist, CP55940. However, at 0.1 nM, O-1184 did not attenuate CP55940-induced inhibition of cyclic AMP production by CB(1-)transfected CHO cells.5 In CB2-transfected CHO cells, cyclic AMP production was inhibited by CP55940 (pEC(50) = 8.59), enhanced by O-1184 and O-584 (pEC(50) = 8.20 and 6.86 respectively) and not significantly affected by O-1238 or O-1315.6 At 100 nM, O-1184 and O-1238 produced surmountable antagonism of CP55940 in CB2 cells, decreasing the pEC(50) of CP55940 from 8.61 to 7.42 (O-1184) or from 8.54 to 7.44 (O-1238).7 These data support the hypothesis that increasing the degree of unsaturation of the aliphatic side-chain of Delta(8)-THC analogues has little effect on CB1 or CB2 receptor affinity but can reduce CB1 receptor efficacy and reverse the direction of responses elicited at CB2 receptors.

AB - 1 We have extended previous investigations of four analogues of Delta(8)-tetrahydrocannabinol (Delta(8)-THC): 6'-azidohex-2'-yne-Delta(8)-THC (O-1184), 6'-azidohex-cis-2'-ene-Delta(8)-THC (O-1238) and octyl-2'-yne-Delta(8)-THC (O-584) and its I-deoxy-analogue (O-1315).2 O-1184, O-1238 and O-584 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 8.28 to 8.45 (CBi) and 8.03 to 8.13 (CB2). The pK(i) values of O-1315 were significantly less, 7.63 (CB1) and 7.01 (CB2).3 All the analogues inhibited forskolin-stimulated cyclic AMP production by CB1-transfected CHO cells(pEC(50) = 9.16 to 9.72). Only O-1238 behaved as a full agonist in this cell line.4 In mouse vasa deferentia, O-1238 inhibited electrically-evoked contractions (pEC(50) = 10.18 and E-max = 70.5%). Corresponding values for O-1184 were 9.08 and 21.1% respectively. At 1 nM, O-1184 produced surmountable antagonism of the cannabinoid receptor agonist, CP55940. However, at 0.1 nM, O-1184 did not attenuate CP55940-induced inhibition of cyclic AMP production by CB(1-)transfected CHO cells.5 In CB2-transfected CHO cells, cyclic AMP production was inhibited by CP55940 (pEC(50) = 8.59), enhanced by O-1184 and O-584 (pEC(50) = 8.20 and 6.86 respectively) and not significantly affected by O-1238 or O-1315.6 At 100 nM, O-1184 and O-1238 produced surmountable antagonism of CP55940 in CB2 cells, decreasing the pEC(50) of CP55940 from 8.61 to 7.42 (O-1184) or from 8.54 to 7.44 (O-1238).7 These data support the hypothesis that increasing the degree of unsaturation of the aliphatic side-chain of Delta(8)-THC analogues has little effect on CB1 or CB2 receptor affinity but can reduce CB1 receptor efficacy and reverse the direction of responses elicited at CB2 receptors.

KW - cannabinoids

KW - cannabinoid CB1 receptors

KW - cannabinoid CB2 receptors

KW - inverse agonism

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

KW - O-1184

KW - mouse vas deferens

KW - SMALL-INTESTINE

KW - CB2 RECEPTORS

KW - PHARMACOLOGY

KW - ACTIVATION

KW - INHIBITION

KW - ANTAGONIST

KW - BINDING

KW - POTENT

U2 - 10.1038/sj.bjp.0702836

DO - 10.1038/sj.bjp.0702836

M3 - Article

VL - 128

SP - 735

EP - 743

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 3

ER -