title: Studies on the adrenergic receptor specificity of inhibitors of phenylethanolamine N-methyltransferase.
abstract: We have examined a series of potent PNMT inhibitors for their selectivity on this enzyme vis'-a-vis other adrenergic receptors for which norepinephrine is also an agonist or substrate. The parent compound, SK&F 64139, inhibits PNMT in the nanomolar range and also has moderate affinity as an alpha 2-adrenoceptor antagonist. Moreover, it possesses very weak activity as an MAO inhibitor and alpha 1-adrenoceptor antagonist. With other compounds in the series, it was possible to retain marked PNMT inhibitory activity while substantially decreasing alpha 2-blocking affinity. These drugs, however, have greater central nervous system (CNS) toxicity than SK&F 64139. It was also possible to substantially enhance the PNMT inhibitory activity of a highly polar compound (SK&UF 29661) without decreasing its receptor specificity, although the resulting analogue contains an additional lipophilic chloro substituent and does, unlike SK&F 29661, penetrate into the CNS.
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001158:Arteries / Q000378:metabolism; D001681:Biological Assay; D003000:Clonidine / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000294:innervation; D009638:Norepinephrine / Q000378:metabolism; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D011817:Rabbits; D011941:Receptors, Adrenergic / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000317:Adrenergic alpha-Antagonists; D011941:Receptors, Adrenergic; D011942:Receptors, Adrenergic, alpha; D010625:Phenylethanolamine N-Methyltransferase; D003000:Clonidine; D009638:Norepinephrine