Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate.
Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 blockade was assessed by the selective removal of functional groups from the structure of diphenoxylate as well as a number of other structural variations. Removal of the nitrile functional group and replacement of the C-4 piperidinyl substituents resulted in several compounds with submicromolar IC(50) values.
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Vic. 3052, Australia.
William
W
Nguyen
Brittany L
BL
Howard
David P
DP
Jenkins
Heike
H
Wulff
Philip E
PE
Thompson
David T
DT
Manallack
D004157:Diphenoxylate / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051664:Kv1.3 Potassium Channel / Q000737:chemistry* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship
D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D004157:Diphenoxylate