title: Synthesis, opioid receptor affinity, and enzymatic hydrolysis of sterically hindered morphine 3-esters.
abstract: With the intention of preparing prodrugs, 10 morphine 3-esters were synthesized and evaluated in vitro for opioid receptor binding and enzymatic hydrolysis. The results of binding assays performed on homogenates of guinea pig brain demonstrate a loss in affinity of morphine to mu-, delta-, and kappa-receptors by esterification at the 3-position. The conversion of the esters to morphine was determined in human plasma by HPLC analysis. The half-lives of hydrolysis ranged from 0.5 to > 300 h. The investigations indicate that esterification at the 3-position results in morphine prodrugs with variable hydrolytic stability. Sterically hindered morphine 3-esters may be a promising approach to manipulate the rate of release of morphine.
authors.affiliation: Department of Pharmacology, University of Kiel, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Mignat
authors.forename: D
authors.initials: D
authors.lastname: Heber
authors.forename: H
authors.initials: H
authors.lastname: Schlicht
authors.forename: A
authors.initials: A
authors.lastname: Ziegler
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004951:Esterification; D006168:Guinea Pigs; D006801:Humans; D006868:Hydrolysis; D009022:Morphine Derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D011957:Receptors, Opioid / Q000378:metabolism*
chemical_list: D009022:Morphine Derivatives; D011957:Receptors, Opioid