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(E)- and (Z)-7-arylidenenaltrexones: synthesis and opioid receptor radioligand displacement assays.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1997 Feb 28; Vol. 40 (5), pp. 749-53. - Publication Year :
- 1997
-
Abstract
- The E-isomer of 7-benzylidenenaltrexone (BNTX, la) was reported by Portoghese as a highly selective delta-opioid antagonist. The corresponding Z-isomer 1b was not readily available through direct aldol condensation of naltrexone (6) with benzaldehyde. Using the photochemical methods employed by Lewis to isomerize cinnamamides, we have obtained Z-isomer 1b in good yield from E-isomer 1a. A series of (E)- and (Z)-7-arylidenenaltrexone derivatives was prepared to study the effect of larger arylidene groups on opioid receptor affinity in this series. By aldol condensation of naltrexone (6) with benzaldehyde, 1-naphthaldehyde, 2-naphthaldehyde, 4-phenylbenzaldehyde, and 9-anthracaldehyde, the (E)-arylidenes were readily obtained. Photochemical isomerization afforded the corresponding Z-isomers. These compounds were evaluated via opioid receptor radioligand displacement assays. In these assays, the Z-isomers generally had higher affinity and were more delta-selective than the corresponding E-isomers. The (Z)-7-(1-naphthylidene)naltrexone (3b) showed the greatest selectivity (delta:mu ratio of 15) and highest affinity delta-binding (Ki = 0.7 nM). PM3 semiempirical geometry optimizations suggest a significant role for the orientation of the arylidene substituent in the binding affinity and delta-receptor selectivity. This work demonstrates that larger groups may be incorporated into the arylidene portion of the molecule with opioid receptor affinity being retained.
- Subjects :
- Animals
Benzomorphans metabolism
Benzylidene Compounds chemical synthesis
Benzylidene Compounds chemistry
Benzylidene Compounds metabolism
Benzylidene Compounds pharmacology
Binding, Competitive
Brain metabolism
Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
Enkephalin, D-Penicillamine (2,5)-
Enkephalins metabolism
Guinea Pigs
Magnetic Resonance Spectroscopy
Mass Spectrometry
Models, Molecular
Molecular Conformation
Molecular Structure
Naltrexone chemical synthesis
Naltrexone chemistry
Naltrexone pharmacology
Narcotic Antagonists chemistry
Narcotic Antagonists metabolism
Narcotic Antagonists pharmacology
Pyrrolidines metabolism
Spectroscopy, Fourier Transform Infrared
Benzeneacetamides
Naltrexone analogs & derivatives
Naltrexone metabolism
Narcotic Antagonists chemical synthesis
Receptors, Opioid, delta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 40
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 9057861
- Full Text :
- https://doi.org/10.1021/jm960573f