LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors

The in vitro pharmacology of a structurally novel compound, LY341495, was investigated at human recombinant metabotropic glutamate (mGlu) receptor subtypes expressed in non-neuronal (RGT, rat glutamate transporter) cells. LY341495 was a nanomolar potent antagonist of 1 S,3 R-1-aminocyclopentane-1,3-...

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Bibliographic Details
Published in:Neuropharmacology 1998, Vol.37 (1), p.1-12
Main Authors: Kingston, A.E, Ornstein, P.L, Wright, R.A, Johnson, B.G, Mayne, N.G, Burnett, J.P, Belagaje, R, Wu, S, Schoepp, D.D
Format: Article
Language:English
Subjects:
Amino Acids - metabolism
Amino Acids - pharmacology
Animals
Biological and medical sciences
cAMP
Cell Line
Colforsin - pharmacology
Cyclic AMP - biosynthesis
Excitatory Amino Acid Antagonists - pharmacology
Glutamatergic system (aspartate and other excitatory aminoacids)
Humans
LY341495
Medical sciences
Metabotropic glutamate receptor antagonist
Metabotropic glutamate receptors
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Phosphoinositide hydrolysis
Prosencephalon - metabolism
Rats
Receptors, Metabotropic Glutamate - antagonists & inhibitors
Receptors, Metabotropic Glutamate - metabolism
Xanthenes - metabolism
Xanthenes - pharmacology
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Summary:The in vitro pharmacology of a structurally novel compound, LY341495, was investigated at human recombinant metabotropic glutamate (mGlu) receptor subtypes expressed in non-neuronal (RGT, rat glutamate transporter) cells. LY341495 was a nanomolar potent antagonist of 1 S,3 R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD)-induced inhibition of forskolin-stimulated cAMP formation at mGlu2 and mGlu3 receptors (respective IC 50s of 0.021 and 0.014 μM). At group I mGlu receptor expressing cells, LY341495 was micromolar potent in antagonizing quisqualate-induced phosphoinositide (PI) hydrolysis, with IC 50 values of 7.8 and 8.2 μM for mGlu1a and mGlu5a receptors, respectively. Among the human group III mGlu receptors, the most potent inhibition of l-2-amino-4-phosphonobutyric acid ( l-AP4) responses was seen for LY341495 at mGlu8, with an IC 50 of 0.17 μM. LY341495 was less potent at mGlu7 (IC 50=0.99 μM) and least potent at mGlu4 (IC 50=22 μM). Binding studies in rat brain membranes also demonstrated nanomolar potent group II mGlu receptor affinity for LY341495, with no appreciable displacement of ionotropic glutamate receptor ligand binding. Thus, LY341495 has a unique range of selectivity across the mGlu receptor subtypes with a potency order of mGlu3≥mGlu2>mGlu8>mGlu7⪢mGlu1a=mGlu5a>mGlu4. In particular, LY341495 is the most potent antagonist yet reported at mGlu2, 3 and 8 receptors. Thus, it represents a novel pharmacological agent for elucidating the function of mGlu receptors in experimental systems.
ISSN:0028-3908
1873-7064
DOI:10.1016/S0028-3908(97)00191-3