(E)- and (Z)-7-Arylidenenaltrexones:  Synthesis and Opioid Receptor Radioligand Displacement Assays

• Published in: Journal of medicinal chemistry Vol. 40; no. 5; pp. 749 - 753
• Main Authors: Palmer, Robert B, Upthagrove, Alana L, Nelson, Wendel L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.02.1997; Amer Chemical Soc
• Subjects: Animals; Benzeneacetamides; Benzomorphans - metabolism; Benzylidene Compounds - chemical synthesis; Benzylidene Compounds - chemistry; Benzylidene Compounds - metabolism; Benzylidene Compounds - pharmacology; Binding, Competitive; Biological and medical sciences; Brain - metabolism; Chemistry, Medicinal; Enkephalin, Ala-MePhe-Gly; Enkephalin, D-Penicillamine (2,5); Enkephalins - metabolism; Guinea Pigs; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Models, Molecular; Molecular Conformation; Molecular Structure; Naltrexone - analogs & derivatives; Naltrexone - chemical synthesis; Naltrexone - chemistry; Naltrexone - metabolism; Naltrexone - pharmacology; Narcotic Antagonists - chemical synthesis; Narcotic Antagonists - chemistry; Narcotic Antagonists - metabolism; Narcotic Antagonists - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrrolidines - metabolism; Receptors, Opioid, delta - metabolism; Science & Technology; Spectroscopy, Fourier Transform Infrared; DESIGN; INHIBITION; MOIETY; LIGANDS; NALTREXONE; RAT; ANTAGONISTS; BINDING; MESSAGE ADDRESS CONCEPT; Morphinan derivatives; Opiate receptor δ; Rodentia; Central nervous system; In vitro; Modeling; Stereoselectivity; Vertebrata; Mammalia; Guinea pig; Structure activity relation; Animal; Molecular model; Affinity; PM3 method; Antagonist; Chemical synthesis; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960573f

The E-isomer of 7-benzylidenenaltrexone (BNTX, 1a) was reported by Portoghese , as a highly selective δ-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 δ-selective than the corresponding E-isomers. The (Z)-7-(1-naphthylidene)naltrexone (3b) showed the greatest selectivity (δ:μ ratio of 15) and highest affinity δ-binding (K i = 0.7 nM). PM3 semiempirical geometry optimizations suggest a significant role for the orientation of the arylidene substituent in the binding affinity and δ-receptor selectivity. This work demonstrates that larger groups may be incorporated into the arylidene portion of the molecule with opioid receptor affinity being retained.