Structural determinants of opioid activity in derivatives of 14-aminomorphinones: effects of changes to the chain linking of the C14-amino group to the aryl ring.
The 14-aminodihydromorphinone and codeinone series of opioid ligands have produced a number of ligands of substantial interest. To investigate the importance of the 14-substituent, a series of analogues in which the side chain length is varied and the amide and alkene functions are reduced have been prepared. Binding affinity, particularly at the mu-opioid receptor (MOR), was largely determined by the aromatic group of the side chain. In the [35S]GTPgammaS functional assay, the ligands having a three-carbon side chain were more potent antagonists than their longer chain counterparts, while shorter, two-carbon chain analogues were of higher MOR efficacy, an effect that was confirmed in vivo. Wash-resistant binding was observed within this series and appeared to be unrelated to side-chain length.
Rennison
David
D
University of Bristol, Cantock's Close, Bristol, BS8 1TS, United Kingdom.
Moynihan
Humphrey
H
Traynor
John R
JR
Lewis
John W
JW
Husbands
Stephen M
SM
D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008024:Ligands; D051379:Mice; D009022:Morphine Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009292:Narcotic Antagonists; D010147:Pain Measurement; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000588:Amines; D000700:Analgesics; D008024:Ligands; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate)