Conformational analysis of the opioid phenylmorphan and its 9 alpha-methyl analogue in solution using high-resolution nuclear magnetic resonance spectroscopy.
The solution conformations of the opioid phenylmorphan (5-m-hydroxyphenyl-2-methylmorphan) and its 9 alpha-methyl analogue were studied using one- and two-dimensional high resolution NMR techniques. The NMR spectra were analyzed by interpreting the phase-sensitive 2-D COSY and double quantum filtered COSY spectra, 1H-1H vicinal coupling constants, and nuclear Overhauser effects in the phase-sensitive 2-D NOESY spectra. The results show that, for both compounds, a chair-chair conformation of the cyclohexane and piperidine rings is exclusively preferred with some distortion of the rings from perfectly staggered chairs. For phenylmorphans, the phenyl ring is oriented to fit into the cleft formed by the cyclohexane and piperidine rings. Thus, for the (+)-enantiomer, the phenyl group assumes the same orientation with regard to the piperidine ring as morphine consistent with the morphine-like properties of the compound. For the 9 alpha-methyl analogue, the plane of the phenyl ring essentially bisects the piperidine ring to which it is attached and is outside of the required range of opioid agonists. This is consistent with the atypical properties of the two enantiomers. The NMR results are compared to the conformations of (-)-phenylmorphan and the (+)-9 alpha-methyl analogue in the crystal state and to the results of molecular mechanics (MM2) studies.
DiMeglio
C M
CM
Section of Medicinal Chemistry and Pharmacognosy, School of Pharmacy/Institute of Materials Science, University of Connecticut, Storrs 06269.
Froimowitz
M
M
Makriyannis
A
A
D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009019:Morphinans / Q000737:chemistry*; D012996:Solutions
D008024:Ligands; D009019:Morphinans; D012996:Solutions; C008075:(-)-5-m-hydroxyphenyl-2-methylmorphan; C040990:2,9-dimethyl-5-(3-hydroxyphenyl)morphan