RT Journal Article SR Electronic T1 Synthesis and Characterization of Potent and Selective Agonists of the Neuronal Cannabinoid Receptor (CB1) JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1427 OP 1433 VO 289 IS 3 A1 Cecilia J. Hillard A1 Sukumar Manna A1 Marcie J. Greenberg A1 Ralph DiCamelli A1 Ruth A. Ross A1 Lesley A. Stevenson A1 Vicki Murphy A1 Roger G. Pertwee A1 William B. Campbell YR 1999 UL http://jpet.aspetjournals.org/content/289/3/1427.abstract 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 (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. The American Society for Pharmacology and Experimental Therapeutics