Bis-catechol-substituted redox-reactive analogues of hexamethonium and decamethonium: stimulated affinity-dependent reactivity through iron peroxide catalysis.
Symmetrically bis-catechol-substituted analogues (1 and 2, respectively) of hexamethonium and decamethonium were synthesized and investigated as redox-activated affinity reagents toward the neurotoxin-binding sites of the nicotinic acetylcholine receptor (nAcChR), purified from Torpedo californica electroplax. These reagents bound to nAcChR with Kd = 1.8 x 10(-8) and 2.3 x 10(-7) M for 1 and 2, respectively. In the presence of a metal, Fe(II)/Fe(III), and peroxide, both reagents produced a rapid and efficient half-of-sites inactivation of neurotoxin-binding sites in the nAcChR in a concentration-dependent manner, which paralleled the extent of receptor binding of the reagents. In the absence of Fe(II)/Fe(III) peroxide, redox-dependent inactivation occurred for both 1 and 2 more slowly and only at concentrations much higher (10(3)-10(4) times) than those necessary to produce significant binding to nAcChR. However, receptor inactivation in the absence of added metal peroxide was still more efficient for 1 and 2 than observed previously for [(trimethylammonio)methyl]catechol (3), the prototypic redox-dependent affinity reagent after which 1 and 2 were patterned. Thus, the new reagents reported are expected to provide more efficient and selective conditions for redox-dependent inactivation at nAcChR and other macromolecular sites to which such reagents may be directed.
Gu
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Department of Medicinal & Biological Chemistry, College of Pharmacy, University of Toledo, Ohio 43606.
Lee
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Hudson
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D000818:Animals; D002384:Catalysis; D002396:Catechols / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D003650:Decamethonium Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D018738:Hexamethonium / Q000378:metabolism; D006584:Hexamethonium Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology*; D018733:Nicotinic Antagonists; D010084:Oxidation-Reduction; D010545:Peroxides / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014101:Torpedo
D002396:Catechols; D003650:Decamethonium Compounds; D006584:Hexamethonium Compounds; D018733:Nicotinic Antagonists; D010545:Peroxides; D011978:Receptors, Nicotinic; C090934:N,N'-(2,3-dihydroxybenzyl)-N,N,N',N'-tetramethyl-1,6-hexanediamine; C090935:N,N'-(2,3-dihydroxy-benzyl)-N,N,N',N'-tetramethyl-1,10-decanediamine; D018738:Hexamethonium; C033019:decamethonium; D007501:Iron