Opioid agonists and antagonists. 6-Desoxy-6-substituted lactone, epoxide, and glycidate ester derivatives of naltrexone and oxymorphone.
Synthesis and opioid radioreceptor assay data on analogues closely related to 6-desoxy-6-spiro-alpha-methylene-gamma-lactone 5a, a compound with irreversible activity in this assay, are reported. Saturated lactones (7a,b), endocyclic alpha, beta-unsaturated gamma-lactones (8a,b and 9a), and 6 alpha,7 alpha-fused alpha-methylene-gamma-lactones (10a and 11a) were prepared. Related 6-desoxy-6-methylene 6 beta- and 6 alpha-oxides (12a,b and 13a) and glycidate esters 14a,b and 15a,b were also prepared with use of naltrexone (1a) and oxymorphone (1b) as starting material. Compounds in the N-cyclopropylmethyl (N-CPM) series were more potent than those in the N-Me series in displacing [3H]naltrexone in the opioid radioreceptor assay, usually by 2-16-fold in the absence of Na ion. The most potent N-CPM analogues were epoxides 12a and 13a and glycidate esters 14a and 15a, showing IC50's of 2-6 nM, similar to that of 5a. Of the N-Me analogues, 6 beta-oxide 12b was most active, with an IC50 of 8 nM in the absence of Na ion. For the N-CPM analogues, the Na ion ratios were generally less than 1, with two exceptions. The N-Me analogues showed expected larger Na ion effects of 7 or greater. None of the lactone analogues had irreversible effects when preincubated in the rat brain membrane preparation, even at 37 degrees C for 30 min, i.e., washing restored [3H]naltrexone binding to control levels. These results clearly show that the alpha-methylene-gamma-lactone moiety of 5a is required for irreversible effects, consistent with it serving as a conjugate addition acceptor of a nucleophilic group from a ligand at or near the receptor. The epoxides and glycidate esters also had no irreversible activity, indicating more electrophilic functional groups are needed and/or these electrophiles are not properly aligned to react with nucleophilic groups at or near the opioid receptor.
G A
GA
Koolpe
W L
WL
Nelson
T L
TL
Gioannini
L
L
Angel
N
N
Appelmans
E J
EJ
Simon
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002942:Circular Dichroism; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D004988:Ethers, Cyclic / Q000138:chemical synthesis*; D004091:Hydromorphone / Q000031:analogs & derivatives*; D007783:Lactones / Q000138:chemical synthesis* / Q000378:metabolism; D008297:Male; D009270:Naloxone / Q000031:analogs & derivatives*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000378:metabolism; D010111:Oxymorphone / Q000031:analogs & derivatives*; D011422:Propionates / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D007783:Lactones; D011422:Propionates; D011957:Receptors, Opioid; D009270:Naloxone; C007869:glycidic acid; D009271:Naltrexone; D010111:Oxymorphone; D004091:Hydromorphone