PMID- 28770024
OWN - NLM
STAT- MEDLINE
DCOM- 20180417
LR  - 20181113
IS  - 1942-0994 (Electronic)
IS  - 1942-0900 (Print)
IS  - 1942-0994 (Linking)
VI  - 2017
DP  - 2017
TI  - Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity.
PG  - 7303096
LID - 10.1155/2017/7303096 [doi]
LID - 7303096
AB  - The results of epidemiological and pathophysiological studies suggest that type 2 
      diabetes mellitus (T2DM) may predispose to Alzheimer's disease (AD). The two 
      conditions present similar glucose levels, insulin resistance, and biochemical 
      etiologies such as inflammation and oxidative stress. The diabetic state also 
      contributes to increased acetylcholinesterase (AChE) activity, which is one of 
      the factors leading to neurodegeneration in AD. The aim of this study was to 
      assess in vitro the effects of metformin, phenformin, and metformin sulfenamide 
      prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE) and 
      establish the type of inhibition. Metformin inhibited 50% of the AChE activity at 
      micromolar concentrations (2.35 mumol/mL, mixed type of inhibition) and seemed to 
      be selective towards AChE since it presented low anti-BuChE activity. The tested 
      metformin prodrugs inhibited cholinesterases (ChE) at nanomolar range and thus 
      were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug 
      demonstrated the highest activity towards both AChE (IC(50) = 890 nmol/mL, 
      noncompetitive inhibition) and BuChE (IC(50) = 28 nmol/mL, mixed type 
      inhibition), while the octyl sulfenamide prodrug did not present anti-AChE 
      activity, but exhibited mixed inhibition towards BuChE (IC(50) = 184 nmol/mL). 
      Therefore, these two bulkier prodrugs were concluded to be the most selective 
      compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides 
      present a novel class of inhibitors for AChE and BuChE and encourages further 
      studies of these compounds for developing both selective and nonselective 
      inhibitors of ChEs in the future.
FAU - Markowicz-Piasecka, Magdalena
AU  - Markowicz-Piasecka M
AUID- ORCID: 0000-0002-1012-6550
AD  - Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis 
      and Radiopharmacy, Medical University of Lodz, ul. Muszynskiego 1, 90-151 Lodz, 
      Poland.
FAU - Sikora, Joanna
AU  - Sikora J
AD  - Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis 
      and Radiopharmacy, Medical University of Lodz, ul. Muszynskiego 1, 90-151 Lodz, 
      Poland.
FAU - Mateusiak, Lukasz
AU  - Mateusiak L
AD  - Students Research Group, Laboratory of Bioanalysis, Department of Pharmaceutical 
      Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. 
      Muszynskiego 1, 90-151 Lodz, Poland.
FAU - Mikiciuk-Olasik, Elzbieta
AU  - Mikiciuk-Olasik E
AD  - Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical 
      University of Lodz, ul. Muszynskiego 1, 90-151 Lodz, Poland.
FAU - Huttunen, Kristiina M
AU  - Huttunen KM
AD  - School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 
      Yliopistonranta 1C, POB 1627 70211 Kuopio, Finland.
LA  - eng
PT  - Journal Article
DEP - 20170709
PL  - United States
TA  - Oxid Med Cell Longev
JT  - Oxidative medicine and cellular longevity
JID - 101479826
RN  - 0 (Cholinesterase Inhibitors)
RN  - 0 (GPI-Linked Proteins)
RN  - 0 (Prodrugs)
RN  - 0 (sulfenamide)
RN  - 9100L32L2N (Metformin)
RN  - EC 3.1.1.7 (ACHE protein, human)
RN  - EC 3.1.1.7 (Acetylcholinesterase)
RN  - EC 3.1.1.8 (Butyrylcholinesterase)
RN  - UR1SAB295F (Sulfamerazine)
SB  - IM
MH  - Acetylcholinesterase/metabolism
MH  - Butyrylcholinesterase/*chemistry/metabolism
MH  - Cholinesterase Inhibitors/*chemistry/pharmacology
MH  - Diabetes Mellitus, Type 2/drug therapy/enzymology
MH  - Female
MH  - GPI-Linked Proteins/antagonists & inhibitors/metabolism
MH  - Humans
MH  - Male
MH  - Metformin/*chemistry/pharmacology
MH  - Prodrugs/*chemistry/pharmacology
MH  - Sulfamerazine/*chemistry/pharmacology
PMC - PMC5523189
EDAT- 2017/08/05 06:00
MHDA- 2018/04/18 06:00
PMCR- 2017/07/09
CRDT- 2017/08/04 06:00
PHST- 2017/03/11 00:00 [received]
PHST- 2017/06/05 00:00 [revised]
PHST- 2017/06/14 00:00 [accepted]
PHST- 2017/08/04 06:00 [entrez]
PHST- 2017/08/05 06:00 [pubmed]
PHST- 2018/04/18 06:00 [medline]
PHST- 2017/07/09 00:00 [pmc-release]
AID - 10.1155/2017/7303096 [doi]
PST - ppublish
SO  - Oxid Med Cell Longev. 2017;2017:7303096. doi: 10.1155/2017/7303096. Epub 2017 Jul 
      9.