title: Syntheses and opioid receptor binding affinities of 8-amino-2,6-methano-3-benzazocines.
abstract: 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.
authors.affiliation: Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180, USA. wentmp@rpi.edu
authors.forename: Mark P
authors.initials: MP
authors.lastname: Wentland
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Ye
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cioffi
authors.forename: Rongliang
authors.initials: R
authors.lastname: Lou
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhou
authors.forename: Guoyou
authors.initials: G
authors.lastname: Xu
authors.forename: Wenhu
authors.initials: W
authors.lastname: Duan
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Dehnhardt
authors.forename: Xufeng
authors.initials: X
authors.lastname: Sun
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Cohen
authors.forename: Jean M
authors.initials: JM
authors.lastname: Bidlack
mesh_terms: 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
chemical_list: 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)