Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1)

C J Hillard, S Manna, M J Greenberg, R Dicamelli, R A Ross, L A Stevenson, V Murphy, R G Pertwee, W B Campbell

Research output: Contribution to journalArticle

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Abstract

Two subtypes of the cannabinoid receptor (CB1 and CB2) are expressed in mammalian tissues. Although selective antagonists are available for each of the subtypes, most of the available cannabinoid agonists bind to both CB1 and CB2 with similar affinities. We have synthesized two analogs of N-arachidonylethanolamine (AEA), arachidonylcyclopropylamide (ACPA) and arachidonyl-2-chloroethylamide (ACEA), that bind to the CB1 receptor with very high affinity (K-I values of 2.2 +/- 0.4 nM and 1.4 +/- 0.3 nM, respectively) and to the CB2 receptor with low affinity (K-I values of 0.7 +/- 0.01 mu M and 3.1 +/- 1.0 mu M, respectively). Both ACPA and ACEA have the characteristics of agonists at the CB1 receptor; both inhibit forskolin-induced accumulation of cAMP in Chinese hamster ovary cells expressing the human CB1 receptor, and both analogs increase the binding of [S-35]GTP gamma S to cerebellar membranes and inhibit electrically evoked contractions of the mouse vas deferens. ACPA and ACEA produce hypothermia in mice, and this effect is inhibited by coadministration of the CBI receptor antagonist SR141716A. Therefore, ACPA and ACEA are high-affinity agonists of the CBI receptor but do not bind the CB2 receptor, suggesting that structural analogs of AEA can be designed with considerable selectivity for the CB1 receptor over the CB2 receptor.

Original languageEnglish
Pages (from-to)1427-1433
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume289
Issue number3
Publication statusPublished - 1 Jun 1999

Keywords

  • RAT-BRAIN MEMBRANES
  • ANANDAMIDE
  • BINDING
  • PHARMACOLOGY
  • MICE
  • ARACHIDONYLETHANOLAMIDE
  • IDENTIFICATION
  • ACTIVATION
  • ANTAGONIST

Cite this

Hillard, C. J., Manna, S., Greenberg, M. J., Dicamelli, R., Ross, R. A., Stevenson, L. A., ... Campbell, W. B. (1999). Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). Journal of Pharmacology and Experimental Therapeutics, 289(3), 1427-1433.

Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). / Hillard, C J ; Manna, S ; Greenberg, M J ; Dicamelli, R ; Ross, R A ; Stevenson, L A ; Murphy, V ; Pertwee, R G ; Campbell, W B .

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 289, No. 3, 01.06.1999, p. 1427-1433.

Research output: Contribution to journalArticle

Hillard, CJ, Manna, S, Greenberg, MJ, Dicamelli, R, Ross, RA, Stevenson, LA, Murphy, V, Pertwee, RG & Campbell, WB 1999, 'Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1)', Journal of Pharmacology and Experimental Therapeutics, vol. 289, no. 3, pp. 1427-1433.
Hillard CJ, Manna S, Greenberg MJ, Dicamelli R, Ross RA, Stevenson LA et al. Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). Journal of Pharmacology and Experimental Therapeutics. 1999 Jun 1;289(3):1427-1433.
Hillard, C J ; Manna, S ; Greenberg, M J ; Dicamelli, R ; Ross, R A ; Stevenson, L A ; Murphy, V ; Pertwee, R G ; Campbell, W B . / Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). In: Journal of Pharmacology and Experimental Therapeutics. 1999 ; Vol. 289, No. 3. pp. 1427-1433.
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AU - Ross, R A

AU - Stevenson, L A

AU - Murphy, V

AU - Pertwee, R G

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AB - Two subtypes of the cannabinoid receptor (CB1 and CB2) are expressed in mammalian tissues. Although selective antagonists are available for each of the subtypes, most of the available cannabinoid agonists bind to both CB1 and CB2 with similar affinities. We have synthesized two analogs of N-arachidonylethanolamine (AEA), arachidonylcyclopropylamide (ACPA) and arachidonyl-2-chloroethylamide (ACEA), that bind to the CB1 receptor with very high affinity (K-I values of 2.2 +/- 0.4 nM and 1.4 +/- 0.3 nM, respectively) and to the CB2 receptor with low affinity (K-I values of 0.7 +/- 0.01 mu M and 3.1 +/- 1.0 mu M, respectively). Both ACPA and ACEA have the characteristics of agonists at the CB1 receptor; both inhibit forskolin-induced accumulation of cAMP in Chinese hamster ovary cells expressing the human CB1 receptor, and both analogs increase the binding of [S-35]GTP gamma S to cerebellar membranes and inhibit electrically evoked contractions of the mouse vas deferens. ACPA and ACEA produce hypothermia in mice, and this effect is inhibited by coadministration of the CBI receptor antagonist SR141716A. Therefore, ACPA and ACEA are high-affinity agonists of the CBI receptor but do not bind the CB2 receptor, suggesting that structural analogs of AEA can be designed with considerable selectivity for the CB1 receptor over the CB2 receptor.

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KW - MICE

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KW - IDENTIFICATION

KW - ACTIVATION

KW - ANTAGONIST

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