Synthesis and evaluation of opioid receptor-binding affinity of elaeocarpenine and its analogs.
Both enantiomers of elaeocarpenine (1) and its analogs, 21, 22, 25, and 27, were synthesized from bicyclic aldehydes 8-10 via a flexible route previously established for total synthesis of grandisines, and their binding affinities for mu-, kappa- and delta-opioid receptor subtypes were evaluated. We found that (9R)-1 exhibited higher affinity than (9S)-1 for all the subtypes, but the enantiomers showed little subtype selectivity. Analogs 21 having a pyrrolizidine skeleton and 27 having a stemona-type skeleton in place of the indolizidine unit of (9S)-1 showed mu-selective and mu-, kappa-selective binding, respectively.
Exploratory Research Laboratories, Kyorin Pharmaceutical Co., Ltd 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Haruaki
H
Kurasaki
Iwao
I
Okamoto
Nobuyoshi
N
Morita
Osamu
O
Tamura
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D006860:Hydrogen Bonding; D007212:Indolizines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D007212:Indolizines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C521036:elaeocarpenine