Celuch S M, Juorio A V
Psychiatric Research Division, University of Saskatchewan, Saskatoon, Canada.
Naunyn Schmiedebergs Arch Pharmacol. 1987 Oct;336(4):391-5. doi: 10.1007/BF00164871.
In spontaneously beating rat atria the potencies for the chronotropic effects of the following deuterated phenylethylamine derivatives were higher than the potencies of the corresponding non-substituted (protio-) amines: alpha,alpha,d2-beta-phenylethylamine; alpha,alpha,beta,beta-d4-p-tyramine; alpha,alpha,beta,beta-d4-m-tyramine; alpha,alpha,beta-d3-p-octopamine. In contrast, alpha,alpha,beta-d3-noradrenaline and alpha,alpha,beta-d3-m-octopamine were equipotent with the corresponding protio-amines. Experiments performed in atria depleted of endogenous noradrenaline by pretreatment with reserpine and in atria exposed to the monoamine oxidase (MAO) inhibitor pargyline indicated: a. p-octopamine had both direct and indirect effects, but the chronotropic responses to p-octopamine in tissues with normal MAO activity depended mostly on the direct action of the amine; deuterium substitution enhanced the indirect component of action of p-octopamine; b. m-octopamine possessed considerable indirect effects while d3-m-octopamine behaved as an amine of direct action. The substitution of deuterium for hydrogens in the alpha-carbon of the alkyl-side chain of phenylethylamines decreases the rate of deamination by MAO. Therefore, the results obtained with all the amines, except for m-octopamine and alpha, alpha,p-d3-m-octopamine, could be interpreted in terms of the direct, indirect or mixed action of those compounds and/or of the influence that MAO activity has on the chronotropic responses to these amines. The results obtained with protio- and deuterio-m-octopamine suggested that deuterium substitution, either at the alpha- or the beta-carbon, can alter some other mechanisms in addition to the enzymatic deamination.
在自发性搏动的大鼠心房中，下列氘代苯乙胺衍生物的变时效应效力高于相应的未取代（原）胺：α,α,d2-β-苯乙胺；α,α,β,β-d4-p-酪胺；α,α,β,β-d4-m-酪胺；α,α,β-d3-p-章鱼胺。相比之下，α,α,β-d3-去甲肾上腺素和α,α,β-d3-m-章鱼胺与相应的原胺效力相当。用利血平预处理使内源性去甲肾上腺素耗竭的心房以及暴露于单胺氧化酶（MAO）抑制剂帕吉林的心房中进行的实验表明：a. p-章鱼胺具有直接和间接作用，但在MAO活性正常的组织中，对p-章鱼胺的变时反应主要取决于胺的直接作用；氘取代增强了p-章鱼胺作用的间接成分；b. m-章鱼胺具有相当大的间接作用，而d3-m-章鱼胺表现为直接作用的胺。苯乙胺烷基侧链α-碳上的氢被氘取代会降低MAO的脱氨速率。因此，除了m-章鱼胺和α,α,p-d3-m-章鱼胺外，所有胺的实验结果都可以根据这些化合物的直接、间接或混合作用和/或MAO活性对这些胺变时反应的影响来解释。原代和氘代m-章鱼胺的实验结果表明，α-或β-碳上的氘取代除了酶促脱氨外，还可以改变一些其他机制。
