Enantiomeric conformers of the opioid agonist ketobemidone HCl in the crystal state.
A crystal of the potent opioid agonist ketobemidone [1-methyl-4-(3-hydroxyphenyl)-4-propionylipiperidine] HCl was analyzed by X-ray crystallography. The crystal was monoclinic, space group P2(1)/n with four molecules in the unit cell. In agreement with MM2 calculations (J. Med. Chem. 25:1127-1133, 1982), the crystal contains mirror image conformers in which the phenyl ring is equatorial to the piperidine ring. The conformers are enantiomers since they are not superimposable. One conformer is predicted to be responsible for the typical morphine-like activity of the compound since it closely matches the preferred conformer of the morphine-like (+)-phenylmorphan whereas the other conformer resembles the preferred conformers of (+)-beta-prodine and (-)-phenylmorphan which have atypical opioid properties and/or structure-activity relationships. The importance of considering the conformational enantiomers of a nonchiral receptor ligand in centrosymmetric crystal structures is emphasized.
Froimowitz
M
M
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02178-9106.
Cody
V
V
D000701:Analgesics, Opioid / Q000737:chemistry*; D003460:Crystallization; D018360:Crystallography, X-Ray / Q000379:methods; D008614:Meperidine / Q000031:analogs & derivatives* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism; D013816:Thermodynamics
D000701:Analgesics, Opioid; D008614:Meperidine; C012394:ketobemidone