Importance of the C-1 substituent in classical cannabinoids to CB2 receptor selectivity: Synthesis and characterization of a series of O,2-propano-Delta(8)-tetrahydrocannabinol analogs

P H Reggio, Tiansheng Wang, Amy E. Brown, Denise N. Fleming, H H Seltzman, G Griffin, Roger Guy Pertwee, D R Compton, M E Abood, Robert Martin

Research output: Contribution to journalArticle

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Abstract

The separation of the mood-altering effects of cannabinoids from their therapeutic effects has been long sought. Results reported here for a series of C-9 analogs of the cyclic ether O,2-propano-Delta(8)-tetrahydrocannabinol (O,2-propano-Delta(8)-THC) point to the C-1 position in classical cannabinoids as a position for which CB2 subtype selectivity occurs within the cannabinoid receptors. O,2-Propano-11-nor-Delta(8)-THC, O,2-propano-Delta(9,11)-THC, O,2-propano-9-oxo-11-norhexahydrocannabinol (O,2-propano-9-oxo-11-nor-HHC), and O,2-propane-9 alpha- and O,2-propane-9 beta-OH-11-nor-HHC were synthesized and evaluated in radioligand displacement assays for affinity at the CB1 and CB2 receptors and in the mouse vas deferens in vitro assay and the mouse tetrad in vivo assay for cannabinoid activity. Evaluation of binding affinity at the CB1 and CB2 receptors revealed that each compound possesses a modest increased affinity for the CB2 receptor. Analogs which contained an oxygen attached to C-9 (i.e., oxo and hydroxy derivatives) showed the highest affinity and selectivity for CB2 (for O,2-propano-9-oxo-11-nor-HHC, K-i(CB1) = 90 nM, K-i(CB2) = 23 nM, selectivity ratio 3.9; for O,2-propano-9 beta-OH-11-nor-HHC, K-i(CB1) = 26 nm, K-i(CB2) = 5.8 nM, selectivity ratio 4.5). Each compound was found to produce a dose-dependent inhibition of electrically-evoked contractions of the mouse isolated vas deferens when administered at submicromolar concentrations. This inhibition could readily be prevented by the selective CB1 cannabinoid receptor antagonist SR-141716A. The analogs exhibited unique in vivo profiles with O,2-propano-Delta(9,11)-THC exhibiting antinociception with reduced activity in three other in vivo measures and O,2-propano-9 beta-OH-HHC exhibiting lack of dose responsiveness in all measures. The CB2 selectivities of the O,2-propano analogs may be due to differences in salvation/desolvation that occur when the ligands enter the CB1 vs CB2 binding site. Alternatively, the CB2 selectivities may be the result of an amino acid change from a hydrogen bond-accepting residue in CB1 to a hydrogen bond-donating residue in CB2.

Original languageEnglish
Pages (from-to)3312-3318
Number of pages7
JournalJournal of Medicinal Chemistry
Volume40
Issue number20
DOIs
Publication statusPublished - 26 Sep 1997

Keywords

  • CANNABIMIMETIC AGENTS
  • ANALGESIC PROPERTIES
  • PHENOLIC HYDROXYL
  • VAS-DEFERENS
  • BINDING
  • PHARMACOLOGY
  • TETRAHYDROCANNABINOLS
  • ANANDAMIDE
  • POTENT
  • BRAIN

Cite this

Importance of the C-1 substituent in classical cannabinoids to CB2 receptor selectivity: Synthesis and characterization of a series of O,2-propano-Delta(8)-tetrahydrocannabinol analogs. / Reggio, P H ; Wang, Tiansheng; Brown, Amy E. ; Fleming, Denise N. ; Seltzman, H H ; Griffin, G ; Pertwee, Roger Guy; Compton, D R ; Abood, M E ; Martin, Robert.

In: Journal of Medicinal Chemistry, Vol. 40, No. 20, 26.09.1997, p. 3312-3318.

Research output: Contribution to journalArticle

Reggio, P H ; Wang, Tiansheng ; Brown, Amy E. ; Fleming, Denise N. ; Seltzman, H H ; Griffin, G ; Pertwee, Roger Guy ; Compton, D R ; Abood, M E ; Martin, Robert. / Importance of the C-1 substituent in classical cannabinoids to CB2 receptor selectivity: Synthesis and characterization of a series of O,2-propano-Delta(8)-tetrahydrocannabinol analogs. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 20. pp. 3312-3318.
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abstract = "The separation of the mood-altering effects of cannabinoids from their therapeutic effects has been long sought. Results reported here for a series of C-9 analogs of the cyclic ether O,2-propano-Delta(8)-tetrahydrocannabinol (O,2-propano-Delta(8)-THC) point to the C-1 position in classical cannabinoids as a position for which CB2 subtype selectivity occurs within the cannabinoid receptors. O,2-Propano-11-nor-Delta(8)-THC, O,2-propano-Delta(9,11)-THC, O,2-propano-9-oxo-11-norhexahydrocannabinol (O,2-propano-9-oxo-11-nor-HHC), and O,2-propane-9 alpha- and O,2-propane-9 beta-OH-11-nor-HHC were synthesized and evaluated in radioligand displacement assays for affinity at the CB1 and CB2 receptors and in the mouse vas deferens in vitro assay and the mouse tetrad in vivo assay for cannabinoid activity. Evaluation of binding affinity at the CB1 and CB2 receptors revealed that each compound possesses a modest increased affinity for the CB2 receptor. Analogs which contained an oxygen attached to C-9 (i.e., oxo and hydroxy derivatives) showed the highest affinity and selectivity for CB2 (for O,2-propano-9-oxo-11-nor-HHC, K-i(CB1) = 90 nM, K-i(CB2) = 23 nM, selectivity ratio 3.9; for O,2-propano-9 beta-OH-11-nor-HHC, K-i(CB1) = 26 nm, K-i(CB2) = 5.8 nM, selectivity ratio 4.5). Each compound was found to produce a dose-dependent inhibition of electrically-evoked contractions of the mouse isolated vas deferens when administered at submicromolar concentrations. This inhibition could readily be prevented by the selective CB1 cannabinoid receptor antagonist SR-141716A. The analogs exhibited unique in vivo profiles with O,2-propano-Delta(9,11)-THC exhibiting antinociception with reduced activity in three other in vivo measures and O,2-propano-9 beta-OH-HHC exhibiting lack of dose responsiveness in all measures. The CB2 selectivities of the O,2-propano analogs may be due to differences in salvation/desolvation that occur when the ligands enter the CB1 vs CB2 binding site. Alternatively, the CB2 selectivities may be the result of an amino acid change from a hydrogen bond-accepting residue in CB1 to a hydrogen bond-donating residue in CB2.",
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TY - JOUR

T1 - Importance of the C-1 substituent in classical cannabinoids to CB2 receptor selectivity: Synthesis and characterization of a series of O,2-propano-Delta(8)-tetrahydrocannabinol analogs

AU - Reggio, P H

AU - Wang, Tiansheng

AU - Brown, Amy E.

AU - Fleming, Denise N.

AU - Seltzman, H H

AU - Griffin, G

AU - Pertwee, Roger Guy

AU - Compton, D R

AU - Abood, M E

AU - Martin, Robert

PY - 1997/9/26

Y1 - 1997/9/26

N2 - The separation of the mood-altering effects of cannabinoids from their therapeutic effects has been long sought. Results reported here for a series of C-9 analogs of the cyclic ether O,2-propano-Delta(8)-tetrahydrocannabinol (O,2-propano-Delta(8)-THC) point to the C-1 position in classical cannabinoids as a position for which CB2 subtype selectivity occurs within the cannabinoid receptors. O,2-Propano-11-nor-Delta(8)-THC, O,2-propano-Delta(9,11)-THC, O,2-propano-9-oxo-11-norhexahydrocannabinol (O,2-propano-9-oxo-11-nor-HHC), and O,2-propane-9 alpha- and O,2-propane-9 beta-OH-11-nor-HHC were synthesized and evaluated in radioligand displacement assays for affinity at the CB1 and CB2 receptors and in the mouse vas deferens in vitro assay and the mouse tetrad in vivo assay for cannabinoid activity. Evaluation of binding affinity at the CB1 and CB2 receptors revealed that each compound possesses a modest increased affinity for the CB2 receptor. Analogs which contained an oxygen attached to C-9 (i.e., oxo and hydroxy derivatives) showed the highest affinity and selectivity for CB2 (for O,2-propano-9-oxo-11-nor-HHC, K-i(CB1) = 90 nM, K-i(CB2) = 23 nM, selectivity ratio 3.9; for O,2-propano-9 beta-OH-11-nor-HHC, K-i(CB1) = 26 nm, K-i(CB2) = 5.8 nM, selectivity ratio 4.5). Each compound was found to produce a dose-dependent inhibition of electrically-evoked contractions of the mouse isolated vas deferens when administered at submicromolar concentrations. This inhibition could readily be prevented by the selective CB1 cannabinoid receptor antagonist SR-141716A. The analogs exhibited unique in vivo profiles with O,2-propano-Delta(9,11)-THC exhibiting antinociception with reduced activity in three other in vivo measures and O,2-propano-9 beta-OH-HHC exhibiting lack of dose responsiveness in all measures. The CB2 selectivities of the O,2-propano analogs may be due to differences in salvation/desolvation that occur when the ligands enter the CB1 vs CB2 binding site. Alternatively, the CB2 selectivities may be the result of an amino acid change from a hydrogen bond-accepting residue in CB1 to a hydrogen bond-donating residue in CB2.

AB - The separation of the mood-altering effects of cannabinoids from their therapeutic effects has been long sought. Results reported here for a series of C-9 analogs of the cyclic ether O,2-propano-Delta(8)-tetrahydrocannabinol (O,2-propano-Delta(8)-THC) point to the C-1 position in classical cannabinoids as a position for which CB2 subtype selectivity occurs within the cannabinoid receptors. O,2-Propano-11-nor-Delta(8)-THC, O,2-propano-Delta(9,11)-THC, O,2-propano-9-oxo-11-norhexahydrocannabinol (O,2-propano-9-oxo-11-nor-HHC), and O,2-propane-9 alpha- and O,2-propane-9 beta-OH-11-nor-HHC were synthesized and evaluated in radioligand displacement assays for affinity at the CB1 and CB2 receptors and in the mouse vas deferens in vitro assay and the mouse tetrad in vivo assay for cannabinoid activity. Evaluation of binding affinity at the CB1 and CB2 receptors revealed that each compound possesses a modest increased affinity for the CB2 receptor. Analogs which contained an oxygen attached to C-9 (i.e., oxo and hydroxy derivatives) showed the highest affinity and selectivity for CB2 (for O,2-propano-9-oxo-11-nor-HHC, K-i(CB1) = 90 nM, K-i(CB2) = 23 nM, selectivity ratio 3.9; for O,2-propano-9 beta-OH-11-nor-HHC, K-i(CB1) = 26 nm, K-i(CB2) = 5.8 nM, selectivity ratio 4.5). Each compound was found to produce a dose-dependent inhibition of electrically-evoked contractions of the mouse isolated vas deferens when administered at submicromolar concentrations. This inhibition could readily be prevented by the selective CB1 cannabinoid receptor antagonist SR-141716A. The analogs exhibited unique in vivo profiles with O,2-propano-Delta(9,11)-THC exhibiting antinociception with reduced activity in three other in vivo measures and O,2-propano-9 beta-OH-HHC exhibiting lack of dose responsiveness in all measures. The CB2 selectivities of the O,2-propano analogs may be due to differences in salvation/desolvation that occur when the ligands enter the CB1 vs CB2 binding site. Alternatively, the CB2 selectivities may be the result of an amino acid change from a hydrogen bond-accepting residue in CB1 to a hydrogen bond-donating residue in CB2.

KW - CANNABIMIMETIC AGENTS

KW - ANALGESIC PROPERTIES

KW - PHENOLIC HYDROXYL

KW - VAS-DEFERENS

KW - BINDING

KW - PHARMACOLOGY

KW - TETRAHYDROCANNABINOLS

KW - ANANDAMIDE

KW - POTENT

KW - BRAIN

U2 - 10.1021/jm970136g

DO - 10.1021/jm970136g

M3 - Article

VL - 40

SP - 3312

EP - 3318

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 20

ER -