(E)- and (Z)-7-arylidenenaltrexones: synthesis and opioid receptor radioligand displacement assays.
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.
Palmer
R B
RB
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195, USA.
Upthagrove
A L
AL
Nelson
W L
WL
D000818:Animals; D044482:Benzeneacetamides; D001575:Benzomorphans / Q000378:metabolism; D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism; D006168:Guinea Pigs; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011759:Pyrrolidines / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017550:Spectroscopy, Fourier Transform Infrared
D044482:Benzeneacetamides; D001575:Benzomorphans; D001597:Benzylidene Compounds; D004745:Enkephalins; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C077358:7-benzylidenenaltrexone; D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-; C027248:bremazocine; C045444:U 69593