HEP (2005) 168:209–246
©cSpringer-Verlag 2005
Structural Requirements for Cannabinoid Receptor Probes
G.A.Thakur·S.P.Nikas·C.Li·A.Makriyannis()
Center for Drug Discovery, Department of Pharmaceutical Sciences,
University of Connecticut, Storrs CT, 06269, USA
[email protected]
1Introduction.................................... 210
2 Classification of Cannabinoid Receptor Ligands ................ 212
2.1 ClassicalCannabinoids .............................. 212
2.1.1SARofClassicalCannabinoids .......................... 212
2.2 Non-classicalCannabinoids............................ 216
2.3 CC/NCCHybridCannabinoids.......................... 217
2.4 Aminoalkylindoles ................................ 218
2.4.1SARofAminoalkylindoles ............................ 219
2.5 Diarylpyrazoles .................................. 223
2.5.1SARofPyrazoleCannabinoidReceptorAntagonists .............. 224
2.6 Endocannabinoids................................. 226
2.6.1SARofEndocannabinoids ............................ 227
2.7 Other Cannabinergic Classes ........................... 231
3 Covalent Binding Probes ............................. 232
4 Enantioselective Cannabinergic Ligands .................... 233
5 Present and Future ................................ 236
References ........................................ 237
AbstractThe discovery and cloning of CB 1 and CB 2 , the two known Gi/oprotein-
coupled cannabinoid receptors, as well as the isolation and characterization of two
familiesofendogenouscannabinergicligandsrepresentedbyarachidonoylethanol-
amide (anandamide) and 2-arachidonoylglycerol (2-AG), have opened new hori-
zons in this newly discovered field of biology. Furthermore, a considerable number
of cannabinoid analogs belonging to structurally diverse classes of compounds
have been synthesized and tested, thus providing substantial information on the
structural requirements for cannabinoid receptor recognition and activation. Ex-
periments with site-directed mutated receptors and computer modeling studies
have suggested that these diverse classes of ligands may interact with the recep-
tors through different binding motifs. The information about the exact binding
site may be obtained with the help of suitably designed molecular probes. These
ligands either interact with the receptors in a reversible fashion (reversible probes)
or alternatively attach at or near the receptor active site with the formation of
covalent bonds (irreversible probes). This review focuses on structural require-