Conjugate addition ligands of opioid antagonists. Methacrylate esters and ethers of 6 alpha- and 6 beta-naltrexol.
Alpha- and beta-naltrexol derived esters 9 and 10 and ethers 11 and 12, each containing the alpha, beta-unsaturated ester functionality, were prepared as conformationally more flexible analogues of spiro-alpha-methylene-gamma-lactones 5 and 6. All were active in the opioid radioreceptor binding assay against [3H]bremazocine and more active against [3H]DAGO, indicating mu-subtype selectivity, but only ether 12 showed significant irreversible activity. We conclude that small structural changes, made in very closely related electrophilic opioids, lead to changes in receptor binding. All four compounds were long-acting antagonists to morphine in mice, with ester 10 being approximately equipotent with naltrexone.
Olsen
L D
LD
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Klein
P
P
Nelson
W L
WL
Yao
Y H
YH
Simon
E J
EJ
D000818:Animals; D001575:Benzomorphans / Q000378:metabolism; D001667:Binding, Competitive; D002417:Cattle; D002421:Caudate Nucleus / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism; D004952:Esters; D004987:Ethers; D066298:In Vitro Techniques; D008024:Ligands; D008689:Methacrylates; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D011957:Receptors, Opioid / Q000187:drug effects*; D013329:Structure-Activity Relationship
D001575:Benzomorphans; D004745:Enkephalins; D004952:Esters; D004987:Ethers; D008024:Ligands; D008689:Methacrylates; D011957:Receptors, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone; C027248:bremazocine