Structural determinants of opioid activity in the orvinols and related structures: ethers of orvinol and isoorvinol.
A series of ethers of orvinol and isoorvinol has been prepared and evaluated in opioid receptor binding and in vitro functional assays. The most striking finding was the very large difference in kappa-opioid receptor activity between the diastereomeric ethyl ethers: 46-fold in binding, 150-fold in GPI, and 900-fold in the [(35)S]GTPgammaS assay in favor of the (R)-diastereomer. Additionally in the (R)-series there was a 700-fold increase in kappa-agonist potency in the [(35)S]GTPgammaS assay when OEt was replaced by OBn. The data can be explained in a triple binding site model: an H-bonding site, a lipophilic site, and an inhibitory site with which the 20-Me group in the (S)-ethers may interact. It appears that kappa-agonist binding of the orvinols avoids the inhibitory site in the intramolecular H-bonded conformation.
Coop
A
A
School of Chemistry, Cantock's Close, University of Bristol, Bristol BS8 1TS, England.
Norton
C L
CL
Berzetei-Gurske
I
I
Burnside
J
J
Toll
L
L
Husbands
S M
SM
Lewis
J W
JW
D000701:Analgesics, Opioid / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009294:Narcotics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism
D000701:Analgesics, Opioid; D006877:Hydroxamic Acids; D009294:Narcotics; D016244:Guanosine 5'-O-(3-Thiotriphosphate)