Selective CB2 agonists with anti-pruritic activity: Discovery of potent and orally available bicyclic 2-pyridones

Functional Activity and Switching of Novel Cannabinergic Ligands

“…261 In the case where amide linkages exist between the aryl groups, S193(5.42) does act as a H-bond donor. 324,325 These interactions may help to provide nsight into why di-protected triaryls do not behave as their di-deprotected counterparts.…”

“…261 In the case where amide linkages exist between the aryl groups, it is suggested that S193(5.42) does act as a H-bond donor. 324,325 4.6.2.2. Hydrophobic and π-π stacking.…”

“…261 More recent 2-pyridone derivatives add additional residues to the binding pocket for π-π stacking, namely Y190(5.39) and F281(7.35) along with C288(7.42). 324,325 For the 2-pyridone analog containing N-butyl, there is a proposed hydrophobic interaction with I198(5.47). 325 Though little data exists, it is suggested that SR-144528 (a CB2-selective inverse agonist) has interaction with W194(5.43) and F197(5.46), 338 which may play a role in stabilizing the inactive state and impart inverse agonist activity.…”

“…324,325 For the 2-pyridone analog containing N-butyl, there is a proposed hydrophobic interaction with I198(5.47). 325 Though little data exists, it is suggested that SR-144528 (a CB2-selective inverse agonist) has interaction with W194(5.43) and F197(5.46), 338 which may play a role in stabilizing the inactive state and impart inverse agonist activity. However, the 2-pyridone shows agonist activity and interaction with W194(5.43) and F197(5.46), so interaction with these residues does not impart inverse agonist activity.…”

“…261 More recent 2-pyridone derivatives add additional residues to the binding pocket for π-π stacking, namely Y190(5.39) and F281(7.35) along with a C288(7.42) residue. 324,325 For the 2-pyridone analog containing N-butyl, there involves a hydrophobic interaction with I198(5.47). hypothesize that the binding mode for the hexahydro series is more similar to THC, in that the ABC ring occupies the tricyclic (ABC ring) pocket of the LBP and the C-3 substituents project into the major pocket.…”