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 (KI values of 2.2 ± 0.4 nM and 1.4 ± 0.3 nM, respectively) and to the CB2 receptor with low affinity (KI values of 0.7 ± 0.01 μM and 3.1 ± 1.0 μM, 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 [35S]GTPγS 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 CB1 receptor antagonist SR141716A. Therefore, ACPA and ACEA are high-affinity agonists of the CB1 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.
Footnotes
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Send reprint requests to: Cecilia J. Hillard, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI. E-mail:chillard{at}mcw.edu
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↵1 This work was supported by National Institutes of Health Grants DA08098 (to C.J.H.), DA09155 (to W.B.C., C.J.H.), and DA09789 (to R.G.P.); Grants 039538 and 047980 from the Wellcome Trust (to R.G.P., R.A.R.); and by a grant from the European Social Fund (to V.M.). A preliminary report of these findings was made at the 1997 meeting of the International Cannabinoid Research Society.
- Abbreviations:
- AEA
- N-arachidonylethanolamine
- CB1
- neuronal cannabinoid receptor
- CB2
- spleen cannabinoid receptor
- CHO
- Chinese hamster ovary
- Δ9-THC
- Δ9-tetrahydrocannabinol
- DMSO
- dimethyl sulfoxide
- ACPA
- arachidonylcyclopropylamide
- ACEA
- arachidonyl-2-chloroethylamide
- TME
- Tris, magnesium, and EDTA
- Received October 20, 1998.
- Accepted February 1, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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