Synthesis of pyridylallylamines related to zimelidine and their inhibition of neuronal monoamine uptake.
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, and SMe. 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-hydroxy[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.
D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D001977:Brompheniramine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D015031:Zimeldine
D001679:Biogenic Amines; D011725:Pyridines; D012701:Serotonin; D015031:Zimeldine; D001977:Brompheniramine; D009638:Norepinephrine