Importance of phenolic address groups in opioid kappa receptor selective antagonists.
In vitro characterization and comparison of JDTic, its dehydroxy analogue and nor-BNI, and its dehydroxy analogue demonstrates that the N-substituted 3,4-dimethyl-(3-hydroxyphenyl)piperidine-derived antagonist, JDTic, relies more heavily on its phenol address group for affinity and antagonist activity relative to the corresponding naltrexone derived antagonists, nor-BNI. The structural flexibility of the former class of compound relative to the latter is postulated to underlie the difference.
Thomas
James B
JB
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
Fix
Scott E
SE
Rothman
Richard B
RB
Mascarella
S Wayne
SW
Dersch
Christina M
CM
Cantrell
Buddy E
BE
Zimmerman
Dennis M
DM
Carroll
F Ivy
FI
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D066298:In Vitro Techniques; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000494:pharmacology
C433814:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide; D010636:Phenols; D010880:Piperidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; C051844:norbinaltorphimine; D009271:Naltrexone