Cannabinoid Receptors and Their Ligands: Ligand–Ligand and Ligand–Receptor Modeling Approaches 251fatty-acid ethanolamides. The first identified ligand of this class was arachi-
donoylethanolamide (AEA, also called anandamide, 4 ) (Devane et al. 1992). AEA
has been shown to be synthesized from lipid in neurons and to be degraded by fatty
acid amide hydrolase (FAAH), an integral membrane protein (Bracey et al. 2002).
2-Arachidonoylglycerol (2-AG; 5 ) was isolated from intestinal tissue and shown to
be a second endogenous CB ligand (CB 1 Ki= 472 ± 55 nM; CB 2 Ki= 1400 ± 172 nM)
(Mechoulam et al. 1995). 2-AG has been found present in the brain at concentra-
tions 170 times greater than anandamide (Stella et al. 1997). In addition, a fatty
acid glycerol ether, 2-arachidonyl glyceryl ether, called noladin ether ( 6 )hasbeen
identified as another endogenous CB ligand (Hanus et al. 2001).
1.2
Cannabinoid CB 1 Receptor Antagonists/Inverse Agonists
The first CB 1 antagonist,N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-
phenyl)-4-methyl-1H-pyrazole-3-carboxamide [SR141716A ( 7 )] was developed by
Rinaldi-Carmona and co-workers at Sanofi Recherche (Rinaldi-Carmona et al.
1994). SR141716A displays nanomolar CB 1 affinity (Ki= 1.98 ± 13 nM), but very
low affinity for CB 2. In vitro, SR141716A antagonizes the inhibitory effects of CB
agonists on both mouse vas deferens contractions and adenylyl cyclase activity
in rat brain membranes. SR141716A also antagonizes the pharmacological and
behavioral effects produced by CB 1 agonists after intraperitoneal (IP) or oral
administration (Rinaldi-Carmona et al. 1994). Several other CB 1 antagonists have
been reported: LY-320135 (Felder et al. 1998), O-1184 (Ross et al. 1998), CP-27,2871
(Meschler et al. 2000), a class of benzocycloheptapyrazoles (Stoit et al. 2002) and,
most recently, a novel series of 3,4-diarylpyrazolines (Lange et al. 2004).
SR141716A ( 7 ) has been shown to act as a competitive antagonist and inverse
agonist in host cells transfected with exogenous CB 1 receptor,aswellasinbi-
ological preparations endogenously expressing CB 1. Bouaboula and co-workers