Syntheses and Opioid Receptor Binding Affinities of 8-Amino-2,6-methano-3-benzazocines

Journal of Medicinal Chemistry
2003.0

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.

Knowledge Graph

Similar Paper

Syntheses and Opioid Receptor Binding Affinities of 8-Amino-2,6-methano-3-benzazocines
Journal of Medicinal Chemistry 2003.0
Redefining the Structure−Activity Relationships of 2,6-Methano-3-benzazocines. 4. Opioid Receptor Binding Properties of 8-[N-(4‘-phenyl)-phenethyl)carboxamido] Analogues of Cyclazocine and Ethylketocycalzocine
Journal of Medicinal Chemistry 2006.0
Redefining the structure–activity relationships of 2,6-methano-3-benzazocines. 5. Opioid receptor binding properties of N-((4′-phenyl)-phenethyl) analogues of 8-CAC
Bioorganic & Medicinal Chemistry Letters 2007.0
Redefining the structure–activity relationships of 2,6-methano-3-benzazocines. Part 7: Syntheses and opioid receptor properties of cyclic variants of cyclazocine
Bioorganic & Medicinal Chemistry Letters 2009.0
Asymmetric Syntheses, Opioid Receptor Affinities, and Antinociceptive Effects of 8-Amino-5,9-methanobenzocyclooctenes, a New Class of Structural Analogues of the Morphine Alkaloids
Journal of Medicinal Chemistry 1996.0
Syntheses and opioid receptor binding properties of carboxamido-substituted opioids
Bioorganic & Medicinal Chemistry Letters 2009.0
Redefining the structure–activity relationships of 2,6-methano-3-benzazocines. Part 6: Opioid receptor binding properties of cyclic variants of 8-carboxamidocyclazocine
Bioorganic & Medicinal Chemistry 2008.0
Redefining the structure–activity relationships of 2,6-methano-3-benzazocines. Part 8. High affinity ligands for opioid receptors in the picomolar Ki range: Oxygenated N-(2-[1,1′-biphenyl]-4-ylethyl) analogues of 8-CAC
Bioorganic & Medicinal Chemistry Letters 2012.0
Selective Protection and Functionalization of Morphine:  Synthesis and Opioid Receptor Binding Properties of 3-Amino-3-desoxymorphine Derivatives<sup>,1</sup>
Journal of Medicinal Chemistry 2000.0
3-Carboxamido analogues of morphine and naltrexone
Bioorganic &amp; Medicinal Chemistry Letters 2001.0