Syntheses and opioid receptor binding affinities of 8-amino-2,6-methano-3-benzazocines.
8-Amino-2,6-methano-3-benzazocine derivatives have been made using Pd-catalyzed amination procedures, and their affinities for opioid receptors were assessed. The 8-amino group was hypothesized to be a replacement for the prototypic 8-OH substituent for 2,6-methano-3-benzazocines and related opiates. This OH group is generally required for binding yet is implicated in unfavorable pharmacokinetic characteristics such as low oral bioavailability and rapid clearance via O-glucuronidation. The core structures in which the 8-OH group was replaced were cyclazocine and its enantiomers, ethylketocyclazocine and its enantiomers, ketocyclazocine, and Mr2034. Many new analogues had high affinity for opioid receptors with several in the subnanomolar range. Highest affinity was seen in analogues with secondary 8-(hetero)arylamino appendages. Binding to opioid receptors was enantioselective with the (2R,6R,11R)-configuration preferred and high selectivity for mu and kappa over delta opioid receptors was observed within the series. Several derivatives were shown to have intrinsic opioid-receptor-mediated activity in [(35)S]GTPgammaS assays.
Wentland
Mark P
MP
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180, USA. wentmp@rpi.edu
Ye
Yingchun
Y
Cioffi
Christopher L
CL
Lou
Rongliang
R
Zhou
Qun
Q
Xu
Guoyou
G
Duan
Wenhu
W
Dehnhardt
Christoph M
CM
Sun
Xufeng
X
Cohen
Dana J
DJ
Bidlack
Jean M
JM
D000818:Animals; D001392:Azocines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008566:Membranes; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013462:Sulfur Radioisotopes
D001392:Azocines; D008024:Ligands; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013462:Sulfur Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate)