PMID- 15867954
OWN - NLM
STAT- MEDLINE
DCOM- 20050613
LR  - 20231013
IS  - 1080-563X (Print)
IS  - 1080-563X (Linking)
VI  - 11
IP  - 1
DP  - 2005 Spring
TI  - LY503430: pharmacology, pharmacokinetics, and effects in rodent models of 
      Parkinson's disease.
PG  - 77-96
AB  - Glutamate is the major excitatory transmitter in the brain. Recent developments 
      in the molecular biology and pharmacology of the 
      alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-subtype of 
      glutamate receptors have led to the discovery of selective, potent and 
      systemically active AMPA receptor potentiators. These molecules enhance synaptic 
      transmission and play important roles in plasticity and cognitive processes. In 
      the present studies we characterized a novel AMPA receptor potentiator, LY503430, 
      on recombinant human GLU(A1-4) and native preparations in vitro, and then 
      evaluated the potential neuroprotective effects of the molecule in rodent models 
      of Parkinson's disease. Results indicated that at submicromolar concentrations 
      LY503430 selectively enhanced glutamate-induced calcium influx into HEK293 cells 
      transfected with human GLU(A1), GLU(A2), GLU(A3), or GLU(A4) AMPA receptors. The 
      molecule also potentiated AMPA-mediated responses in native cortical, hippocampal 
      and substantia nigra neurones. LY503430 had good oral bioavailability in both 
      rats and dogs. We also report here that LY503430 provided dose-dependent 
      functional and histological protection in animal models of Parkinson's disease. 
      The neurotoxicity following unilateral infusion of 6-hyrdoxydopamine (6-OHDA) 
      into either the substantia nigra or the striatum of rats and that following 
      systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice were 
      reduced. Interestingly, LY503430 also had neurotrophic actions on functional and 
      histological outcomes when treatment was delayed until well after (6 or 14 days) 
      the lesion was established. LY503430 also produced some increase in brain derived 
      neurotrophic factor (BDNF) in the substantia nigra and a dose-dependent increase 
      in growth associated protein-43 (GAP-43) expression in the striatum. Therefore, 
      we propose that AMPA receptor potentiators such as LY503430 offer the potential 
      of a new disease modifying therapy for Parkinson's disease.
FAU - O'Neill, Michael J
AU  - O'Neill MJ
AD  - Eli Lilly and Co., Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, 
      Surrey, GU20 6PH, UK. Oneill_Michael_J@Lilly.com
FAU - Murray, Tracey K
AU  - Murray TK
FAU - Clay, Michael P
AU  - Clay MP
FAU - Lindstrom, Terry
AU  - Lindstrom T
FAU - Yang, Charles R
AU  - Yang CR
FAU - Nisenbaum, Eric S
AU  - Nisenbaum ES
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - CNS Drug Rev
JT  - CNS drug reviews
JID - 9514898
RN  - 0 
      ((R)-4'-(1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl)-biphenyl-4-carboxylic 
      acid methylamide)
RN  - 0 (Amides)
RN  - 0 (Biphenyl Compounds)
RN  - 0 (Growth Substances)
RN  - 0 (Receptors, Glutamate)
SB  - IM
MH  - *Amides/chemistry/pharmacokinetics/pharmacology/therapeutic use
MH  - Animals
MH  - Behavior, Animal/drug effects
MH  - *Biphenyl Compounds/chemistry/pharmacokinetics/pharmacology/therapeutic use
MH  - *Disease Models, Animal
MH  - Dogs
MH  - Dose-Response Relationship, Drug
MH  - Drug Interactions
MH  - Growth Substances/metabolism
MH  - Humans
MH  - In Vitro Techniques
MH  - Neurites/drug effects/physiology
MH  - Neurons/drug effects
MH  - Parkinson Disease/*drug therapy/metabolism
MH  - Prefrontal Cortex/cytology
MH  - Rats
MH  - Receptors, Glutamate/drug effects/genetics
MH  - Rodentia
PMC - PMC6741716
EDAT- 2005/05/04 09:00
MHDA- 2005/06/14 09:00
PMCR- 2005/03/01
CRDT- 2005/05/04 09:00
PHST- 2005/05/04 09:00 [pubmed]
PHST- 2005/06/14 09:00 [medline]
PHST- 2005/05/04 09:00 [entrez]
PHST- 2005/03/01 00:00 [pmc-release]
AID - CNS77 [pii]
AID - 10.1111/j.1527-3458.2005.tb00037.x [doi]
PST - ppublish
SO  - CNS Drug Rev. 2005 Spring;11(1):77-96. doi: 10.1111/j.1527-3458.2005.tb00037.x.