Synthesis and opioid receptor activity of indolopropellanes.
A series of skeletal rearranged indolomorphinans 7a-d were obtained by N-demethylation of 3-methoxy-N-methyl-14-hydroxymorphinan-6-one 12 followed by N-realkylation, reduction and Fischer indole cyclization. The structure of the novel skeleton was confirmed by X-ray analysis. These new indoles displayed moderate binding affinity and selectivity at the mu receptor, with compound 7b showing the highest affinity at this receptor with a K(i) value of 40nM, and 6- and 25-fold selectivity against delta and kappa receptors, respectively. Function assays showed that indolopropellanes 7b and 7c possessed full agonistic activity at all the opioid receptors indicating a different interaction model existed.
Li
Fuying
F
Synthetic Organic and Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Gaob
Linghuan
L
Yin
Chenlei
C
Chen
Jie
J
Liu
Jinggen
J
Xie
Xin
X
Zhang
Ao
A
D018360:Crystallography, X-Ray; D008968:Molecular Conformation; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship
D009019:Morphinans; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma