Cannabinoid Receptors and Their Ligands: Ligand–Ligand and Ligand–Receptor Modeling Approaches 255indicated that the protons of hydroxyl groups at positions corresponding to the
C11 position of 1 may interact with an electronegative acceptor atom.
3.1.1
Side Chain SAR
One of the molecular regions of the classical/non-classical CBs that has been the
focusofrecentinterestistheC-3alkylsidechain.Severalgroupshavelookedatthe
effect of the introduction of unsaturation or functionality in the alkyl side chain
of classical CBs. 1′,1′-Cyclopropyl side chain substituents were found to enhance
the affinities of (–)-∆^8 -tetrahydrocannabinol (∆^8 -THC) and respective cannabidiol
analogs for the CB 1 and CB 2 cannabinoid receptors (Papahatjis et al. 2002). For
novel analogs of∆^8 -THC ( 9 )inwhichtheconformationofthesidechainwas
restricted by incorporating the first one or two carbons into a six-membered ring
fused with the aromatic phenolic ring, results indicated that the “southbound”
chain conformer retained the highest affinity for both receptors (Khanolkar et al.
1999). Papahatjis and co-workers (1998) published a study involving side chain-
constrained analogs of∆^8 -THC, including a 3-(1-heptynyl) analog synthesized in a
β-11-HHC ( 10 ) series and a potent 1′-dithiolane derivative. No analog had the side
chaininafullyrestrictedconformation.However,theauthorsconcludedfromtheir
binding data, and in particular the increased potency of the 1′-dithiolane and the
1 ′-methylene analogs, that a hydrophobic subsite of the CB pharmacophore exists
in both CB 1 and CB 2 at the level of the benzylic side chain carbon. To study the