(Tétrahydro-1,2,3,6 pyridinyl-4)-3 1H-indoles: synthèse, propriétés sérotoninergique et anti-dopaminergiques

Abstract

The synthesis of a series of 3-(1,2,3,6-tetrahydro pyridin-4-yl) 1H-indoles and the study of their serotoninergic and/or anti-dopaminergic properties are reported. Most of the compounds have been obtained by condensation of the piperidones II on the indole derivatives I in acidic or alkaline medium. The products have been tested in vitro for their binding to dopaminergic and serotoninergic receptors and in animals for gross behavior experiments as well as for drug interactions (apomorphine induced stereotypies and emesis, prochlorperazine induced catalepsy and 5-HT syndrome). The biological activities are largely dependent upon the nitrogen substitution of the tetrahydropyridinic ring and on the nature of the 5-substituent. The secondary amines VI exhibited, in general, both serotoninergic and dopaminergic agonist properties. In this case, the highest activity is reached for derivatives with OCH 3 or SCH 3 in the 5 position. On the other hand, the tertiary amines VII having an ethyl, propyl or cyclopropylmethyl on the nitrogen showed dopamine blocking activities. This activity becomes stronger with the increasing electro-attractive effect of the 5-substituent (X = NO 2 > Cl > H > SCH 3 > OCH 3). In the N-propyl series (VII R = nC 3H 7), a direct correlation between the dopaminergic effect and the Hammett parameter σp of the substituent X has been established. The 5-methoxy secondary amine VI (X = 5-OCH 3, RU 24969) and the 5-chloro N-propyl derivative VII (X = 5-Cl, R = nC 3H 7, RU 27592) have been more extensively studied in order to determine their mechanism of action and their possible clinical application in the field of psychotropic drugs.