Discovery of an opioid kappa receptor selective pure antagonist from a library of N-substituted 4beta-methyl-5-(3-hydroxyphenyl)morphans.
A library of compounds biased toward opioid receptor antagonist activity was prepared by incorporating N-phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)morphans as the core scaffold using simultaneous solution phase synthetic methodology. From this library, N-phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)-7alpha-[3-(1-piperidinyl)propanamido]morphan [(-)-3b] was identified as the first potent and selective kappa opioid receptor antagonist from the 5-phenylmorphan class of opioids.
Thomas
James B
JB
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
Atkinson
Robert N
RN
Namdev
Nivedita
N
Rothman
Richard B
RB
Gigstad
Kenneth M
KM
Fix
Scott E
SE
Mascarella
S Wayne
SW
Burgess
Jason P
JP
Vinson
N Ariane
NA
Xu
Heng
H
Dersch
Christina M
CM
Cantrell
Buddy E
BE
Zimmerman
Dennis M
DM
Carroll
F Ivy
FI
D000818:Animals; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D009019:Morphinans; C463523:N-phenylpropyl-4-methyl-5-(3-hydroxyphenyl)-7-(3-(1-piperidinyl)propanamido)morphan; D017473:Receptors, Opioid, kappa