Synthesis, opioid receptor affinity, and enzymatic hydrolysis of sterically hindered morphine 3-esters.
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.
Mignat
C
C
Department of Pharmacology, University of Kiel, Germany.
Heber
D
D
Schlicht
H
H
Ziegler
A
A
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*
D009022:Morphine Derivatives; D011957:Receptors, Opioid