Faculty Collaboration Database

Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J Pharmacol Exp Ther 1999 Jun;289(3):1427-33

Date

05/21/1999

Pubmed ID

10336536

DOI

10.1016/s0022-3565(24)38289-8

Scopus ID

2-s2.0-0033060910 (requires institutional sign-in at Scopus site)   336 Citations

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 microM and 3.1 +/- 1.0 microM, 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]GTPgammaS 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.

Author List

Hillard CJ, Manna S, Greenberg MJ, DiCamelli R, Ross RA, Stevenson LA, Murphy V, Pertwee RG, Campbell WB

Authors

William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Cecilia J. Hillard PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenylyl Cyclases
Animals
Arachidonic Acids
Binding, Competitive
Body Temperature
CHO Cells
Cannabinoids
Cerebellum
Cricetinae
Cyclohexanols
Electric Stimulation
Guanosine 5'-O-(3-Thiotriphosphate)
Humans
In Vitro Techniques
Kinetics
Male
Mice
Mice, Inbred ICR
Mice, Inbred Strains
Muscle Contraction
Muscle, Smooth
Neurons
Receptors, Cannabinoid
Receptors, Drug
Recombinant Proteins
Transfection
Vas Deferens