Neuroleptics from the 4a,9b-cis- and 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole series. 2.
Compounds derived from 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4, 3-b]indole are consistently efficacious in displacing [3H]spiroperidol from striatal dopamine receptors in vitro. Derivatives bearing substituents at position 2, particularly those derived from butyrophenone moieties, are exceptionally potent in vivo. Compounds from the corresponding 4a,9b-cis series are substantially less potent in both in vivo and in vitro assays of neuroleptic activity. Although the cis and trans derivatives have, in some conformations, similar basic nitrogen atom to aromatic ring separations of about 5.1 A, the distance at which the basic nitrogen atom lies above or below the plane of the aromatic ring differs substantially between the two series. Consideration of these results in terms of this and earlier work indicates that the out-of-plane distance for the basic nitrogen in neuroleptic molecules may range from about 0 to about 0.90 A but may be optimized at about 0.55 A.
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D002243:Carbolines; D011954:Receptors, Dopamine