Structure-activity relationships of some opiate glycosides.
A number of analogues of morphine-6-glucuronide 1 have been prepared and evaluated as potential analgesic agents by competitive mu-receptor binding assay and in vivo antinociceptive activity. The analogues show variation in the nature of the carbohydrate residue, the N-substituent, the O(3)-substituent and saturation of the 7,8-double bond compared to 1. In general, only the 6beta-glucoside or beta-glucuronide carbohydrate residues showed potent agonism; other modified carbohydrates were less active or exhibited potential antagonism. Variations in N-substituent led to either reduced agonism (N-H) or potential antagonism [N-allyl, N-(cyclopropyl)methyl]; a polar N-substituent, carboxymethyl, failed to bind. Saturation of the 7,8-double bond led to increased agonism compared to the parent compound in all three examples studied.
Stachulski
Andrew V
AV
Ultrafine UFC Ltd, Synergy House, Guildhall Close, Manchester Science Park, Manchester M15 6SY, UK. stachuls@liverpool.ac.uk
Scheinmann
Feodor
F
Ferguson
John R
JR
Law
Jayne L
JL
Lumbard
Keith W
KW
Hopkins
Peter
P
Patel
Naina
N
Clarke
Simon
S
Gloyne
Anna
A
Joel
Simon P
SP
D000818:Animals; D002240:Carbohydrate Sequence; D003061:Codeine / Q000031:analogs & derivatives / Q000494:pharmacology; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009022:Morphine Derivatives / Q000737:chemistry; D009294:Narcotics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects; D013329:Structure-Activity Relationship
D006027:Glycosides; D009022:Morphine Derivatives; D009294:Narcotics; D017450:Receptors, Opioid, mu; C035349:morphine-6-glucuronide; D003061:Codeine