PMID- 18220329
OWN - NLM
STAT- MEDLINE
DCOM- 20080519
LR  - 20141120
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 51
IP  - 4
DP  - 2008 Feb 28
TI  - Vesicular monoamine transporter substrate/inhibitor activity of MPTP/MPP+ 
      derivatives: a structure-activity study.
PG  - 760-8
LID - 10.1021/jm070875p [doi]
AB  - The active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 
      N-methyl-4-phenylpyridinium (MPP(+)), selectively destroys the dopaminergic 
      neurons and induces the symptoms of Parkinson's disease. Inhibition of 
      mitochondrial complex I and/or the perturbation of dopamine metabolism through 
      cellular and granular accumulation have been proposed as some of the major causes 
      of neurotoxicity. In the present study we have synthesized and characterized a 
      number of MPTP and MPP(+) derivatives that are suitable for the comparative 
      neurotoxicity and complex I inhibition versus dopamine metabolism perturbation 
      studies. Structure-activity studies with bovine chromaffin granule ghosts show 
      that 3'-hydroxy-MPP(+) is one of the best known substrates for the vesicular 
      monoamine transporter (VMAT). A series of compounds that combine the structural 
      features of MPP(+) and a previously characterized VMAT inhibitor, 
      3-amino-2-phenyl-propene, have been identified as the most effective VMAT 
      inhibitors. These derivatives have been used to define the structural 
      requirements of the VMAT substrate and inhibitor activities.
FAU - Wimalasena, D Shyamali
AU  - Wimalasena DS
AD  - Department of Chemistry, Wichita State University, Wichita, Kansas 67260-0051, 
      USA.
FAU - Perera, Rohan P
AU  - Perera RP
FAU - Heyen, Bruce J
AU  - Heyen BJ
FAU - Balasooriya, Inoka S
AU  - Balasooriya IS
FAU - Wimalasena, Kandatege
AU  - Wimalasena K
LA  - eng
GR  - NS 39423/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080126
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Vesicular Monoamine Transport Proteins)
RN  - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
RN  - R865A5OY8J (1-Methyl-4-phenylpyridinium)
SB  - IM
MH  - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/*analogs & derivatives/*chemical 
      synthesis/pharmacology
MH  - 1-Methyl-4-phenylpyridinium/*analogs & derivatives/*chemical 
      synthesis/pharmacology
MH  - Animals
MH  - Cattle
MH  - Chromaffin Granules/drug effects/metabolism
MH  - Crystallography, X-Ray
MH  - In Vitro Techniques
MH  - Models, Molecular
MH  - Structure-Activity Relationship
MH  - Vesicular Monoamine Transport Proteins/*antagonists & inhibitors/metabolism
EDAT- 2008/01/29 09:00
MHDA- 2008/05/20 09:00
CRDT- 2008/01/29 09:00
PHST- 2008/01/29 09:00 [pubmed]
PHST- 2008/05/20 09:00 [medline]
PHST- 2008/01/29 09:00 [entrez]
AID - 10.1021/jm070875p [doi]
PST - ppublish
SO  - J Med Chem. 2008 Feb 28;51(4):760-8. doi: 10.1021/jm070875p. Epub 2008 Jan 26.