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

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Abstract
Analogs of the antidepressant agent zimelidine [6, (Z)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridyl)allylamine], a selective inhibitor of neuronal 5-hydroxytryptamine [5-HT] reuptake, were synthesized by several routes to obtain compounds having a cis configuration (with respect to pyridyl and allylamine). Two methods used suitably substituted benzoylpyridines as starting materials. In 2 other routes, the bromine in 6 was either directly displaced (CN) or converted via the corresponding lithio derivative to H, Cl, I, Me SiMe3 and SMe. The configurations were determined by UV, 1H NMR, and La-induced shifts in 1H NMR. The compounds were evaluated as uptake inhibitors by measuring the accumulation of [3H]noradrenaline [norepinephrine, NE] and 5-hydroxy[14C]tryptamine in mouse brain slices (in vitro and in vivo). Para-substitution favored 5-HT activity and ortho-substitution favored NE activity in the cis series. The in vitro effect on 5-HT was insensitive to variations in the para substituent, whereas pronounced effects in vivo were observed only with Cl, Br (6) and I.

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