Probes for narcotic receptor mediated phenomena. Part 28: new opioid antagonists from enantiomeric analogues of 5-(3-hydroxyphenyl)-N-phenylethylmorphan.
Enantiomeric analogues of 5-(3-hydroxyphenyl)morphan ligands were synthesized and evaluated because of our unexpected finding that opioid antagonists can be obtained in the 5-phenylmorphan series of opioids without sterically hindering the rotation of the phenolic ring. We determined the opioid receptor binding affinity of these new analogues, as well as the efficacy of the more interesting ligands. One of the new compounds [(1R,5S)-(-)-3-[2-(3'-phenylpropyl)-2-azabicyclo[3.3.1]non-5-yl]-phenol, 15] was found to have half of the efficacy of naloxone, a potent opioid antagonist, in the [(35)S]GTPgammaS assay, and two others (1R,5S)-(-)-3-[2-(4'-phenylbutyl)-2-azabicyclo[3.3.1]non-5-yl]-phenol, 17, and (1R,5S,1'S)-(+)-3-[2-(1'-methyl-2'-phenylethyl)-2-azabicyclo[3.3.1]non-5-yl]-phenol, 26, acted as moderately potent opioid antagonists. X-ray crystallographic structure data were obtained on three compounds. Two of them had three chiral centers; 25 [(1R,5S,1'R)-(-)-3-[2-(1'-methyl-2'-phenylethyl)-2-azabicyclo[3.3.1]non-5-yl]-phenol] was determined to have the 1R,5S,1'R configuration, and 26 the 1R,5S,1'S configuration. Since (1S,5R)-(+)-2-bromo-5-[2-(2'-phenylethyl)-2-azabicyclo[3.3.1]non-5-yl]-phenol (32) was a position isomer of (1S,5R)-(+)-4-bromo-3-[2-(2'-phenylethyl)-2-azabicyclo[3.3.1]non-5-yl]-phenol (30), and both showed the same 1H NMR spectrum, the structure of 32 was unequivocally determined by X-ray structure analysis.
Hashimoto
Akihiro
A
Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0815, USA.
Jacobson
Arthur E
AE
Rothman
Richard B
RB
Dersch
Christina M
CM
George
Clifford
C
Flippen-Anderson
Judith L
JL
Rice
Kenner C
KC
D000818:Animals; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D015335:Molecular Probes / Q000138:chemical synthesis / Q000493:pharmacokinetics; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011957:Receptors, Opioid / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C475852:5-(3-hydroxyphenyl)-N-phenylethylmorphan; D015335:Molecular Probes; D009019:Morphinans; D009292:Narcotic Antagonists; D011957:Receptors, Opioid