Högberg T, Ulff B, Renyi A L, Ross S B
J Med Chem. 1981 Dec;24(12):1499-507. 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, 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.
抗抑郁药齐美利定[6, (Z)-3-(4-溴苯基)-N,N-二甲基-3-(3-吡啶基)烯丙胺]是一种神经元5-羟色胺再摄取的选择性抑制剂，为了获得具有顺式构型（相对于吡啶基和烯丙胺）的化合物，通过几种途径合成了其类似物。两种方法使用适当取代的苯甲酰吡啶作为起始原料。在另外两条路线中，6中的溴要么直接被取代（CN），要么通过相应的锂衍生物转化为H、Cl、I、Me、SiMe3和SMe。构型通过紫外光谱、1H核磁共振以及1H核磁共振中的镧系元素诱导位移来确定。通过测量小鼠脑切片（体外和体内）中[3H]去甲肾上腺素和5-羟基[14C]色胺的积累，将这些化合物评估为摄取抑制剂。在顺式系列中，对位取代有利于5-羟色胺活性，邻位取代有利于去甲肾上腺素活性。对5-羟色胺的体外作用对对位取代基的变化相当不敏感，而仅在使用Cl、Br（6）和I时在体内观察到显著作用。
