Cannabinoid Receptors and Their Ligands: Ligand–Ligand and Ligand–Receptor Modeling Approaches 2573.2
Ligand–Receptor Studies for Classical/Non-classical CB Binding to CB 1
Shim and co-workers recently published a ligand–receptor study in which a molec-
ular docking approach that combined Monte Carlo and molecular dynamics sim-
ulations was used to identify putative binding conformations of non-classical CB
agonists, including AC-bicyclic CP-47,497 and CP-55,940 ( 2 ), and ACD-tricyclic
CP-55,244 (Shim et al. 2003). These investigators used an inactive state model of
CB 1 for these docking studies based upon the X-ray crystal structure of rhodopsin
(Palczewski et al. 2000). Ligand placement was based upon the assumption of
acriticalhydrogenbondbetweentheA-ringOHandthesidechainNofLys192
in transmembrane helix (TMH) 3. Two alternative binding conformations were
considered, with a conformation in which the C-3 side chain pointed inside the re-
ceptor chosen as the binding site conformation for which the ligand could achieve
more interactions. Key hydrogen bonds were identified between both K3.28(192)
and E(258) and the A-ring OH (see 2 ), and between Q(261) and the C-ring C-12
hydroxypropyl.
3.3
CB 2 Selective Classical/Non-classical CBs Break CB 1 SAR rules
In recent years, it has become clear that one way to develop CB 2 -selective com-
pounds is to violate long accepted pharmacophore requirements for binding to CB 1
(see consensus pharmacophore list above). In particular, CB 2 -selective compounds
have emerged through changes in the phenolic hydroxyl region and through short-
ening of the alkyl side chain.
3.3.1
Phenolic Hydroxyl
Huffman was first to show that removal of the phenolic hydroxyl of 11-hydroxy-∆^8 -
tetrahydrocannabinol-1′,1′-dimethylheptyl (HU-210, 12 ) results in a CB 2 -selective
compound ( 13 )withhighaffinityforboththeCB 1 and CB 2 receptors (CB 1
Ki= 1.2 ± 0.1 nM, CB 2 Ki= 0.032 ± 0.019 nM) (Huffman et al. 1996). In addition,
Gareau reported that the conversion of the C-1 phenolic hydroxyl of a classical
CB to a methoxy group (i.e., etherification) also produced a CB 2 -selective ligand
(Gareau et al. 1996). In both of these studies, analogs possessed a longer side chain
than natural CBs, a 1′,1′-dimethylheptyl (DMH) side chain at C-3. Huffman and
co-workers also showed that removal of the 11-hydroxy group of deoxy-HU-210
to produce deoxy-∆^8 -THC-DMH still resulted in a ligand with good CB 1 affinity
(CB 1 Ki= 23 ± 7 nM) and CB 2 selectivity (CB 2 Ki= 2.9 ± 1.6 nM) (Huffman et al.
1996). O,2-propano-9β-OH-11-nor-HHC ( 14 ), a rigidified C-1 ether, has also been
reported to have good CB 1 affinity (Ki= 26 ± 2 nM) and a 4.5-fold CB 2 selectivity
(Ki= 5.8 ± 2.9 nM) (Reggio et al. 1997).