PMID- 25844489
OWN - NLM
STAT- MEDLINE
DCOM- 20160315
LR  - 20180105
IS  - 1948-7193 (Electronic)
IS  - 1948-7193 (Linking)
VI  - 6
IP  - 6
DP  - 2015 Jun 17
TI  - Selectivity and anti-Parkinson's potential of thiadiazolidinone RGS4 inhibitors.
PG  - 911-9
LID - 10.1021/acschemneuro.5b00063 [doi]
AB  - Many current therapies target G protein coupled receptors (GPCR), transporters, 
      or ion channels. In addition to directly targeting these proteins, disrupting the 
      protein-protein interactions that localize or regulate their function could 
      enhance selectivity and provide unique pharmacologic actions. Regulators of G 
      protein signaling (RGS) proteins, especially RGS4, play significant roles in 
      epilepsy and Parkinson's disease. Thiadiazolidinone (TDZD) inhibitors of RGS4 are 
      nanomolar potency blockers of the biochemical actions of RGS4 in vitro. Here, we 
      demonstrate the substantial selectivity (8- to >5000-fold) of CCG-203769 for RGS4 
      over other RGS proteins. It is also 300-fold selective for RGS4 over GSK-3beta, 
      another target of this class of chemical scaffolds. It does not inhibit the 
      cysteine protease papain at 100 muM. CCG-203769 enhances Galphaq-dependent cellular 
      Ca(2+) signaling in an RGS4-dependent manner. TDZD inhibitors also enhance 
      Galphai-dependent delta-OR inhibition of cAMP production in SH-SY-5Y cells, which express 
      endogenous receptors and RGS4. Importantly, CCG-203769 potentiates the known RGS4 
      mechanism of Galphai-dependent muscarinic bradycardia in vivo. Furthermore, it 
      reverses raclopride-induced akinesia and bradykinesia in mice, a model of some 
      aspects of the movement disorder in Parkinson's disease. A broad assessment of 
      compound effects revealed minimal off-target effects at concentrations necessary 
      for cellular RGS4 inhibition. These results expand our understanding of the 
      mechanism and specificity of TDZD RGS inhibitors and support the potential for 
      therapeutic targeting of RGS proteins in Parkinson's disease and other neural 
      disorders.
FAU - Blazer, Levi L
AU  - Blazer LL
AD  - daggerDepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, 
      Michigan 48109, United States.
FAU - Storaska, Andrew J
AU  - Storaska AJ
AD  - daggerDepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, 
      Michigan 48109, United States.
AD  - double daggerDepartment of Pharmacology and Toxicology, Michigan State University, East 
      Lansing, Michigan 48824, United States.
FAU - Jutkiewicz, Emily M
AU  - Jutkiewicz EM
AD  - daggerDepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, 
      Michigan 48109, United States.
FAU - Turner, Emma M
AU  - Turner EM
AD  -  section signDepartment of Pharmacy and Pharmacology, University of Bath, Bath, U.K.
FAU - Calcagno, Mariangela
AU  - Calcagno M
AD  -  parallelSection of Pharmacology, Department of Medical Science, University of Ferrara, 
      Ferrara, Italy 44121.
FAU - Wade, Susan M
AU  - Wade SM
AD  - daggerDepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, 
      Michigan 48109, United States.
FAU - Wang, Qin
AU  - Wang Q
AD  - daggerDepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, 
      Michigan 48109, United States.
FAU - Huang, Xi-Ping
AU  - Huang XP
AD  -  perpendicularNational Institute of Mental Health Psychoactive Drug Screening Program (NIMH 
      PDSP), Department of Pharmacology, University of North Carolina, Chapel Hill, 
      North Carolina 27599, United States.
FAU - Traynor, John R
AU  - Traynor JR
AD  - daggerDepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, 
      Michigan 48109, United States.
FAU - Husbands, Stephen M
AU  - Husbands SM
AD  -  section signDepartment of Pharmacy and Pharmacology, University of Bath, Bath, U.K.
FAU - Morari, Michele
AU  - Morari M
AD  -  parallelSection of Pharmacology, Department of Medical Science, University of Ferrara, 
      Ferrara, Italy 44121.
FAU - Neubig, Richard R
AU  - Neubig RR
AD  - double daggerDepartment of Pharmacology and Toxicology, Michigan State University, East 
      Lansing, Michigan 48824, United States.
LA  - eng
GR  - R01 GM039561/GM/NIGMS NIH HHS/United States
GR  - R21 NS067617/NS/NINDS NIH HHS/United States
GR  - R01 GM110195/GM/NIGMS NIH HHS/United States
GR  - R03 MH087441/MH/NIMH NIH HHS/United States
GR  - R01 DA023252/DA/NIDA NIH HHS/United States
GR  - HHSN-271-2013-00017-C/PHS HHS/United States
GR  - R21 NS057014/NS/NINDS NIH HHS/United States
GR  - P30 CA046592/CA/NCI NIH HHS/United States
GR  - T32GM008597/GM/NIGMS NIH HHS/United States
GR  - P60 DK020572/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150420
PL  - United States
TA  - ACS Chem Neurosci
JT  - ACS chemical neuroscience
JID - 101525337
RN  - 0 (Antiparkinson Agents)
RN  - 0 (Cholinergic Agonists)
RN  - 0 (RGS Proteins)
RN  - 175335-35-0 (RGS4 protein)
RN  - 430K3SOZ7G (Raclopride)
RN  - 8Y164V895Y (Carbachol)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 2.7.11.1 (GSK3B protein, human)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, mouse)
RN  - EC 2.7.11.1 (Gsk3b protein, rat)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - EC 3.4.22.2 (Papain)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Antiparkinson Agents/*pharmacology
MH  - Bradycardia/drug therapy/physiopathology
MH  - Calcium/metabolism
MH  - Carbachol/pharmacology
MH  - Cell Line, Tumor
MH  - Cholinergic Agonists/pharmacology
MH  - Cyclic AMP/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Glycogen Synthase Kinase 3/metabolism
MH  - Glycogen Synthase Kinase 3 beta
MH  - HEK293 Cells
MH  - Humans
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Motor Activity/drug effects/physiology
MH  - Papain/metabolism
MH  - Parkinsonian Disorders/drug therapy/physiopathology
MH  - RGS Proteins/*antagonists & inhibitors/metabolism
MH  - Raclopride
MH  - Rats, Sprague-Dawley
OTO - NOTNLM
OT  - PPI
OT  - Parkinson's disease
OT  - RGS
OT  - Regulator of G-protein signaling
OT  - protein-protein interaction
OT  - thiadiazolidinone
EDAT- 2015/04/07 06:00
MHDA- 2016/03/16 06:00
CRDT- 2015/04/07 06:00
PHST- 2015/04/07 06:00 [entrez]
PHST- 2015/04/07 06:00 [pubmed]
PHST- 2016/03/16 06:00 [medline]
AID - 10.1021/acschemneuro.5b00063 [doi]
PST - ppublish
SO  - ACS Chem Neurosci. 2015 Jun 17;6(6):911-9. doi: 10.1021/acschemneuro.5b00063. 
      Epub 2015 Apr 20.