Inhibition of choline transport by redox-active cholinomimetic bis-catechol reagents.
Both N,N'-(2,3-dihydroxybenzyl)-N,N,N',N'-tetramethyl-1,6-hexanediamine dibromide (DTH, 6) and N,N'-(2,3-dihydroxybenzyl)-N,N,N',N'-tetramethyl-1,10-decanediamine dibromide (DTD, 7), which are symmetrical bis-catechol substituted hexamethonium and decamethonium analogues, respectively, were found to inhibit high-affinity choline transport in mouse brain synaptosomes. Inhibitory properties were evaluated using an extraordinarily sensitive capillary electrophoresis method employing electrochemical detection at an enzyme-modified microelectrode. Dose-response curves were generated for each inhibitor and IC(50) values were determined to be 76 microM for 6 and 21 microM for 7. Lineweaver-Burk analysis revealed that both molecules inhibit high-affinity choline uptake by a mixed inhibition mechanism. The K(I) values for 6 and 7 were determined to be 73+/-1 and 31+/-2 microM, respectively. The inhibition properties were further compared to a series of mono-catechol analogues, 3-[(trimethylammonio)methyl]catechol (1), N,N-dimethylepinephrine (4) and 6-hydroxy-N,N-dimethylepinephrine (5), as well as the well-characterized hemicholinium inhibitors, hemicholinium-15 (HC-15, 8) and hemicholinum-3 (HC-3, 9).
Cai
Shuang
S
Department of Chemistry, College of Arts and Sciences, The University of Toledo, Toledo, OH 43606, USA.
Mukherjee
Jhindan
J
Tillekeratne
L M Viranga
LM
Hudson
Richard A
RA
Kirchhoff
Jon R
JR
D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology*; D002794:Choline / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000493:pharmacokinetics; D018678:Cholinergic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D019075:Electrophoresis, Capillary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008839:Microelectrodes; D015394:Molecular Structure; D010084:Oxidation-Reduction; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism