Synthesis and biological activity of 8beta-substituted hydrocodone indole and hydromorphone indole derivatives.
The 8beta-unsubstituted and substituted analogues of hydrocodone indole and hydromorphone indole were synthesized and their binding affinities to opioid receptors were determined. Introduction of an 8beta-methyl group into the indolomorphinan nucleus increased affinity at all opioid receptors. 6,7-Dehydro-4,5alpha-epoxy-8beta-methyl-6,7,2',3'-indolomorphinan (9) was found to be a delta antagonist with subnanomolar affinity (0.7 nM) for the delta-opioid receptor, and to have good delta-selectivity (mu/delta=322).
Yu
Han
H
Laboratory of Medicinal Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.
Prisinzano
Thomas
T
Dersch
Christina M
CM
Marcus
Jamila
J
Rothman
Richard B
RB
Jacobson
Arthur E
AE
Rice
Kenner C
KC
D006853:Hydrocodone / Q000737:chemistry*; D004091:Hydromorphone / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects; D013329:Structure-Activity Relationship
D007211:Indoles; D011957:Receptors, Opioid; D006853:Hydrocodone; D004091:Hydromorphone