Discovery of the first N-substituted 4beta-methyl-5-(3-hydroxyphenyl)morphan to possess highly potent and selective opioid delta receptor antagonist activity.
A structurally novel opioid delta receptor selective antagonist has been identified. This compound, (+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl-(1-phenyl-1-cyclopentane)carboxamide [(+)-KF4, (+)-4], showed a K(e) value of 0.15 nM in the [(35)S]GTPgammaS functional assay. (+)-KF4 is also a delta inverse agonist with an IC(50) value of 1.8 nM. To our knowledge, this is the first potent and selective delta opioid receptor antagonist from the 5-phenylmorphan class of opioids.
Carroll
F Ivy
FI
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA. fic@rti.org
Zhang
Li
L
Mascarella
S Wayne
SW
Navarro
Hernán A
HA
Rothman
Richard B
RB
Cantrell
Buddy E
BE
Zimmerman
Dennis M
DM
Thomas
James B
JB
D000818:Animals; D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C482215:5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo(3.3.1)non-7-yl-(1-phenyl-1-cyclopentane)carboxamide; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017465:Receptors, Opioid, delta