Dopaminergic (4aR,10bS)-cis- and (4aS,10bS)-trans-octahydrobenzo[F]quinolines have similar pharmacophores.
The structures and absolute configurations of two N-phenethyl substituted cis- and trans-octahydrobenzo[f]quinolines were determined by X-ray crystallography. The absolute configurations of the enantiomers that have high affinity for dopaminergic receptors were found to be (4aR,10bS) and (4aS,10bS) for the (-)-cis- and (-)-trans-8,9-dihydroxy substituted compounds. This is consistent with previous results for a dopamine agonist pharmacophore. MM2-87 calculations for a cis isomer, which has two alternative chair conformations of the piperidine ring, indicated that the preferred conformer is the same as that observed in the crystal structure. Superposition of the more active cis and trans enantiomers showed that the three dimensional orientations of the phenyl ring and the ammonium group are similar in the two geometrical isomers. The cis isomer, however, has steric bulk out of the plane of the molecule and this appears to result in a loss of agonist efficacy. The addition of the N-phenethyl group to the 7-OH and 7,8-diOH cis compounds, however, appears to be sufficient to restore high affinity for dopaminergic receptors unlike previously synthesized cis compounds. These cis compounds, however, appear to be mixed agonist/antagonists or antagonists on functional assays of dopaminergic activity.
Froimowitz
M
M
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, MA 02178, USA.
Deng
Y
Y
Jacob
J N
JN
Li
N
N
Cody
V
V
D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015259:Dopamine Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism
D016227:Benzoquinones; D015259:Dopamine Agents