- Significant progress was made since the last reporting, and numerous papers were published. In one important article, we describe the synthesis and pharmacology of novel high-affinity mu opioid antagonists. The synthesis method is simple with high yield. Such agents could be developed as medications for the treatment of opioid addiction and overdose. Probes for narcotic receptor mediated phenomena. 44. Synthesis of an N-substituted 4-hydroxy-5-(3-hydroxyphenyl)morphan with high affinity and selective μ-antagonist activity. (2012) Eur. J. Med Chem. 50:44-54. A simple three-step synthesis of 5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo3.3.1nonan-4-ol (3a) was achieved using an osmium tetroxide mediated oxidation of the known intermediate 6. A pyrrolidine-ring variant of 3a (3-(7-(hydroxymethyl)-6-methyl-6-azabicyclo3.2.1octan-1-yl)phenol (5)) was isolated when other routes were used. The epimeric hydroxy analogue 4a was synthesized by simple inversion of the stereochemistry at C-4. Both N-methyl (3a and 4a) and N-phenethyl (3b and 4b) derivatives were synthesized. The compounds were examined for their opioid receptor affinity and the N-phenethyl analogue 3b was found to have relatively weak affinity for the μ-opioid receptor (K(i) = 74 nM). However, the N-phenethyl analogue of the C-4 epimer, 4b, had about 15 fold higher affinity than 3b and was selective for the μ-opioid receptor (K(i) = 4.6 nM). Compound 4b was a moderately potent μ-opioid antagonist (K(e) = 12 nM), as determined by (35)SGTP-γ-S assays. Compounds 3b and 4b were energy minimized at the level of B3LYP/6-31G*, and then overlaid onto the 5-phenylmorphan, the (1R,5R,9S)-(-)-enantiomer of 2b (Fig. 1) with the αor β-OH group at the C-9 position. The spatial orientation of the hydroxyl moiety in 3b, 4b, 2a, and 2b is proposed to be the structural requirement for high μ-opioid receptor binding affinity and their agonist or antagonist activity. The modest change in spatial position of the hydroxyl moiety, and not the N-substituent, induced the change from potent agonist to an antagonist of moderate potency.
|Sally, Elliott J; Xu, Heng; Dersch, Christina M et al. (2010) Identification of a novel ""almost neutral"" micro-opioid receptor antagonist in CHO cells expressing the cloned human mu-opioid receptor. Synapse 64:280-8|
|Rutherford, John M; Wang, Jiabei; Xu, Heng et al. (2008) Evidence for a mu-delta opioid receptor complex in CHO cells co-expressing mu and delta opioid peptide receptors. Peptides 29:1424-31|
|Prisinzano, Thomas E; Rothman, Richard B (2008) Salvinorin A analogs as probes in opioid pharmacology. Chem Rev 108:1732-43|
|Tidgewell, Kevin; Groer, Chad E; Harding, Wayne W et al. (2008) Herkinorin analogues with differential beta-arrestin-2 interactions. J Med Chem 51:2421-31|
|Xu, Heng; Wang, Xiaoying; Partilla, John S et al. (2008) Differential effects of opioid agonists on G protein expression in CHO cells expressing cloned human opioid receptors. Brain Res Bull 77:49-54|