Design, synthesis, and X-ray data of novel potential antipsychotic agents. Substituted 7-phenylquinolizidines: stereospecific, neuroleptic, and antinociceptive properties.
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, in addition, leaves open many opportunities for variations. Whereas the initial compound 5a, modeled after the structure of butaclamol, was virtually inactive, the introduction of substituents 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: (9aH)-2-tert-butyl-7-(2,4-dichlorophenyl)octahydro-2H-qui nolizin-2-ol (5e). By the optical resolution of 5c, it was demonstrated 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, e.g., (2R,7S,9aS)-2-butylocta-hydro-7-phenyl-2H-quinolizin-2 -yl acetate [(+)-26]. Interestingly, this compound belongs to the enantiomeric series opposite to that of the neuroleptic-like (-)-5e.
D000698:Analgesia; D000700:Analgesics; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002069:Butaclamol / Q000378:metabolism; D018492:Dopamine Antagonists; D008297:Male; D008968:Molecular Conformation; D011807:Quinolizines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011954:Receptors, Dopamine; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D000700:Analgesics; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D011807:Quinolizines; D011954:Receptors, Dopamine; C040362:2-tert-butyl-7-(2,4-dichlorophenyl)octahydro-2H-quinolizin-2-ol; D002069:Butaclamol