HEP (2005) 168:247–281
©cSpringer-Verlag 2005
Cannabinoid Receptors and Their Ligands: Ligand–Ligand
and Ligand–Receptor Modeling Approaches
P.H. Regg io
Department of Chemistry and Biochemistry, University of North Carolina Greensboro,
P.O. Box 26170, Greensboro NC, 27402, USA
[email protected]
1Introduction.................................... 248
1.1 CannabinoidReceptorAgonists ......................... 250
1.2 Cannabinoid CB 1 ReceptorAntagonists/InverseAgonists ........... 251
1.3 CB 2 Antagonists.................................. 252
2 CB Pharmacophore Development:
Ligand–Ligand and Ligand–Receptor Approaches ............... 252
3 Classical/Non-classical CB Pharmacophores .................. 254
3.1 Ligand–Ligand Studies:
CoMFAPharmacophoresforClassical/Non-classicalCBs............ 254
3.1.1SideChainSAR .................................. 255
3.2 Ligand–Receptor Studies for Classical/Non-classical CB Binding to CB 1 .... 257
3.3 CB 2 Selective Classical/Non-classical CBs Break CB 1 SARrules ........ 257
3.3.1PhenolicHydroxyl ................................ 257
3.3.2SideChain ..................................... 259
4 Endogenous CB Pharmacophores ........................ 259
4.1 EndocannabinoidSAR .............................. 260
4.1.1AcylChainSAR .................................. 260
4.1.2HeadGroupSAR.................................. 261
4.2 Ligand–LigandStudiesofEndocannabinoids .................. 262
4.2.1TestsofCoMFAModels .............................. 263
4.3 Ligand–ReceptorModelingStudiesofEndocannabinoidBinding ....... 263
5 Aminoalkylindole Pharmacophores....................... 265
5.1 Ligand–Ligand Studies of the Aminoalkylindoles and Related Compounds.. 266
5.2 Ligand–ReceptorStudiesofAminoalkylindoleBinding............. 269
6 SR141716A Pharmacophores........................... 270
6.1 Ligand–Ligand Studies of SR141716A.. .................... 270
6.2 Ligand–Receptor Models for SR141716A Binding ................ 272
6.3 SAR of Other Recently Synthesized CB 1 Antagonists .............. 272
7Conclusions.................................... 273
References ........................................ 273
AbstractThecannabinoidCB 1 andCB 2 receptorsbelongtotheclassA,rhodopsin-
like family of GPCRs. Antagonists for each receptor sub-type, as well as four
structural classes of agonists that bind to both receptors, have been identified.