STUDIES ON THE ADRENERGIC-RECEPTOR SPECIFICITY OF INHIBITORS OF PHENYLETHANOLAMINE N-METHYLTRANSFERASE

  • 1 January 1981
    • journal article
    • research article
    • Vol. 34  (3) , 399-408
Abstract
A series of potent PNMT [phenylethanolamine-N-methyltransferase] inhibitors were examined for their selectivity on this enzyme in relation to other adrenergic receptors for which norepinephrine is also an agonist or substrate. The parent compound, SK&F 64139 [7,8-dichloro-1,2,3,4-tetraisoquinoline hydrochloride) inhibits [rabbit adrenal] PNMT in the nanomolar range and also has moderate affinity as an .alpha.2-adrenoceptor antagonist. It possesses very weak activity as a MAO [monoamine oxidase] inhibitor and .alpha.1-adrenoceptor antagonist. With other compounds in the series, it was possible to retain marked PNMT inhibitory activity while substantially ddecreasing .alpha.2-blocking affinity. These drugs have greater CNS toxicity than SK&F 64139. It was also possible to substantially enhance the PNMT inhibitory activity of a highly polar compound [SK&F 29661, 1,2,3,4-tetrahydro-7-isoquinolinesulfanamide] without decreasing its receptor specificity, although the resulting analog contains an additional lipophilic chloro substituent and does, unlike SK&F 29661, penetrate into the CNS.

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