Synthesis and Pharmacological Evaluation of Some New Tetrahydroisoquinoline Derivatives Inhibiting Dopamine Uptake and/or Possessing a Dopaminomimetic Property

Article abstract of DOI:10.1021/jm00157a012

As shown by structure-activity relationship studies in 8-(substituted-amino)-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines, the most important structural requirement for a marked antidepressant action is a presence of an ureido, (alkoxycarbonyl)amino, or <(alkylamino)acyl>amino group attached to the isoquinoline skeleton in position 8.In one of the biological test a significant difference was found between 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (nomifensine) and the new compounds synthesized.Nearly all compounds substituted in the amino group either decrease the spontaneous motility in mice or exert no effect on it.Two syntheses have been elaborated for the preparation of the compounds represented by the general formulas II-V where R¹ = hydrogen, halogen, or methyl; Y = CONHR, OCOR, or CO(CH2)nNHR, in which R = alkyl or aralkyl or NHR = cyclic amine and n = 1-2.The syntheses start either from the corresponding 8-amino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines or from the corresponding noncyclized amino alcohols.Of the compounds, 4-(p-chlorophenyl)-8-<(ethoxycarbonyl)amino>-2-methyl-1,2,3,4-tetrahydroisoquinoline was found to possess the highest activity.