Design, synthesis, and x-ray data of novel potential antipsychotic agents. Substituted 7-phenylquinolizidines: stereospecific, neuroleptic, and antinociceptive properties

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Abstract
The semirigid 7-phenylquinolizidine system was selected for the design of new potential antipsychotic agents because it fulfills earlier considerations on the minimal structural and steric requirements necessary to attain a high affinity to the dopamine receptors and leaves open many opportunities for variations. Whereas the initial compound modeled after the structure of butaclamol, was virtually inactive, the introduction of substitutents on the phenyl ring and of further optional structural elements improved the dopamine antagonistic properties by supplying additional binding forces. Initially, a compound in the potency range of chlorpromazine was obtained, i.e., (9aH)-2-tert-butyl-7-(2,4-dichlorophenyl)octahydro-2H-quinolizin-2-ol (5e). Optical resolution showed that the biological activity resides in the (-)-enantiomer. The absolute configuration of (-)-5e was determined by single-crystal X-ray analysis to be 2S,7R,9aR. Further variations of the optional structural elements led to the unexpected finding of compounds with strong antinociceptive properties in rats, e.g., (2R,7S,9aS)-2-butyloctahydro-7-phenyl-2H-quinolizin-2-yl acetate [(+)-25]. This compound belongs to the enantiomeric series opposite to that of the neuroleptic-like (-)-5e.