Synthesis of pyridylallylamines related to zimelidine and their inhibition of neuronal monoamine uptake

Article abstract of DOI:10.1021/jm00144a025

Analogues of the antidepressant agent zimelidine [6, (Z)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridyl)allylamine], a selective inhibitor of neuronal 5-hydroxytryptamine reuptake, were synthesized by several routes with the aim of obtaining compounds having a cis configuration (with respect to pyridyl and allylamine). Two methods utilized suitably substituted benzoylpyridines as starting materials. In two other routes, the bromine in 6 was either directly displaced (CN) or converted via the corresponding lithio derivative to H, Cl, I, Me, SiMe₃. The configurations were determined by UV, ¹H NMR and lanthanide-induced shifts in ¹H NMR. The compounds were evaluated as uptake inhibitors by measuring the accumulation of [³H]noradrenaline and 5-hydroxyl[¹⁴C]tryptamine in mouse brain slices (in vitro and in vivo). Para substitution favored 5-hydroxytryptamine activity and ortho substitution favored NA activity in the cis series. The in vitro effect on 5-hydroxytryptamine was rather insensitive to variations in the para substituent, whereas pronounced effects in vivo were observed only with Cl, Br (6), and I.