Thiouracil antithyroid drugs as a new class of neuronal nitric oxide synthase inhibitors.
Two established antithyroid drugs, 6-propyl-2-thiouracil and 6-methyl-2-thiouracil, as well as S-methylthiouracil, are shown to be competitive inhibitors of nitric oxide synthase (NOS) (K(I) values ranging from 14 to 60 microM), with moderate selectivity for the neuronal isoform. Other thioureylene and thioamide-containing heterocyclic systems proved virtually ineffective as NOS inhibitors. Besides offering novel useful leads for inhibitor design as well as to probe the active site of neuronal NOS, the results of this study may have interesting implications in relation to the antithyroid activity of thiouracils and their possible neurological effects.
Palumbo
A
A
Zoological Station "Anton Dohrn,", Naples, Villa Comunale, I-80121, Italy. palumbo@alpha.szn.it
d'Ischia
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M
D000818:Animals; D013956:Antithyroid Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D002531:Cerebellum / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D006418:Heme / Q000378:metabolism; D066298:In Vitro Techniques; D008954:Models, Biological; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D013329:Structure-Activity Relationship; D013889:Thiouracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D013956:Antithyroid Agents; D004791:Enzyme Inhibitors; D001708:Biopterins; D006418:Heme; D013889:Thiouracil; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; C003402:sapropterin