Chemistry of opium alkaloids. Part 44: synthesis and opioid receptor binding profile of substituted ethenoisomorphinans and ethenomorphinans.
7- and 8-substituted 6alpha,14alpha-ethenoisomorphinans were synthesized by reaction of properly substituted morphinan-6,8-dienes (analogues of thebaine) with methyl vinyl ketone or ethyl acrylate. Reaction with the appropriate Grignard reagent gave the 7- and 8-dialkylmethanols, respectively. Cleavage of the 3-methyl ether with KOH/glycol or boron tribromide afforded the 3-hydroxyl derivatives. In general, the compounds with the ethoxycarbonyl or dimethylmethanol substituent at the 8alpha-position showed lower affinity for the mu, kappa, and delta opioid receptor subtypes than the corresponding 7alpha- and 7beta-substituted compounds. Introduction of a chloro substituent in position 18 increased the potency significantly. The 7-substituent could be connected to the 18-position without loss of affinity. 5Beta-alkyl substitution of 6alpha,14alpha-ethenoisomorphinans led to a decrease in affinity for the three opioid receptor subtypes. In the 5beta-methyl series the affinity for the mu and delta receptors increased from 7alpha-dimethylmethanol to 7alpha-methylhexylmethanol. In the 5beta-alkyl series, the affinity for the mu-receptor could be increased by connecting the 5- and 7-substituents, yielding a compound with high mu-selectivity. The new 6beta,14beta-ethenomorphinans did not show affinity for any of the opioid receptors, in accordance with the inactivity earlier found in in vivo experiments.
Maat
L
L
Laboratory of Organic Chemistry and Catalysis, Delft University of Technology, The Netherlands. L.maat@stm.tudelft.nl
Woudenberg
R H
RH
Meuzelaar
G J
GJ
Linders
J T
JT
D000818:Animals; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011957:Receptors, Opioid / Q000378:metabolism*
D009019:Morphinans; D011957:Receptors, Opioid