3-Deoxyclocinnamox: the first high-affinity, nonpeptide mu-opioid antagonist lacking a phenolic hydroxyl group.
The C(3)-substituent in morphinan opioids is of critical importance; the 3-OH group is usually associated with very much higher affinity for mu-receptors than H or -OMe. However in this series of 14beta-cinnamoylamino derivatives the codeinones (e.g. methoclocinnamox, MC-CAM) had unexpectedly high mu-opioid receptor affinity, similar to that of the morphinone (clocinnamox, C-CAM). The current report relates to the synthesis and in vitro evaluation of deoxyclocinnamox (DOC-CAM) which acted as a high-affinity opioid antagonist similar to C-CAM but with greater mu selectivity. Thus it appears that the C(3)-substituent does not play a major role in the binding of the 14beta-cinnamoyl series and that the cinnamoyl group itself may in fact be the dominant binding feature.
Derrick
I
I
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
Neilan
C L
CL
Andes
J
J
Husbands
S M
SM
Woods
J H
JH
Traynor
J R
JR
Lewis
J W
JW
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D003001:Cloning, Molecular; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D009022:Morphine Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
C413354:3-deoxyclocinnamox; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate)