title: Synthesis and opioid receptor affinity of a series of aralkyl ethers of 6 alpha- and 6 beta-naltrexol.
abstract: A series of 6-O-ethers of 6 beta- and 6 alpha-naltrexol (6 and 7) were prepared to examine the effect of large aralkyl groups on affinity of the ligands for opioid receptors. The affinities of the 6 beta- and 6 alpha-O-ether with benzyl, biphenylmethyl, 1- and 2-naphthylmethyl, and 9-anthracylmethyl groups were determined. Preparation of the ligands was accomplished from suitably 3-O-protected derivatives of 6 and 7 by phase transfer catalyzed alkylation using aralkyl halides, followed by deprotection. Both 3-O-trityl and -benzyl protecting groups were used. In radioligand displacement assays, compounds from the 6 alpha-O ether series had higher affinity than the analogous diastereomers in the 6 beta-O series, with few exceptions. In the 6 alpha-O series, the benzyl ether (29) and the biphenylmethyl ether (30) had the highest affinity, similar to naltrexone. In the 6 beta-O series, the benzyl ether had the highest affinity. The larger aralkyl ethers had slightly less affinity. Large lipophilic 6 beta-O- and 6 alpha- O-aralkyl groups are readily accommodated in the drug-receptor interaction.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
authors.forename: T D
authors.initials: TD
authors.lastname: Nelson
authors.forename: R D
authors.initials: RD
authors.lastname: Davis
authors.forename: W L
authors.initials: WL
authors.lastname: Nelson
mesh_terms: D000478:Alkylation; D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004987:Ethers / Q000138:chemical synthesis* / Q000378:metabolism; D006168:Guinea Pigs; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004987:Ethers; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone