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A novel, competitive mGlu 5 receptor antagonist (LY344545) blocks DHPG‐induced potentiation of NMDA responses but not the induction of LTP in rat hippocampal slices
Author(s) -
Doherty A J,
Palmer M J,
Bortolotto Z A,
Hargreaves A,
Kingston A E,
Ornstein P L,
Schoepp D D,
Lodge D,
Collingridge G L
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703574
Subject(s) - long term potentiation , nmda receptor , metabotropic receptor , glutamate receptor , ampa receptor , pharmacology , biology , receptor , receptor antagonist , competitive antagonist , kainate receptor , antagonist , chemistry , biochemistry
We have investigated the pharmacological properties of LY344545, a structurally related epimer of the broad spectrum competitive metabotropic glutamate receptor antagonist, LY341495. We have found that LY344545 also antagonizes competitively nearly all mGlu receptor subtypes, but with a wide spectrum of activity. The order of potency for the human receptor isoforms was mGlu 5a (IC 50 of 5.5±0.6 μ M )>mGlu 2 =mGlu 3 >mGlu 1α =mGlu 7 >mGlu 6 =mGlu 8 . No significant mGlu 4 receptor antagonist activity was detected at the highest concentration used (100 μ M ). 100 μ M LY344545 displaced 50±5% of [ 3 H]‐CGP39653 binding, but less than 30% of [ 3 H]‐kainate or [ 3 H]‐AMPA in radioligand binding assays. LY344545 antagonized L ‐glutamate stimulated Ca 2+ release in CHO cells transfected with mGlu receptors in a concentration dependent manner with a 10 fold higher affinity for the rat mGlu 5a receptor ( K i =2.1±0.6 μ M ) compared to the rat mGlu 1α receptor ( K i =20.5±2.1 μ M ). 50 μ M (1S, 3R)‐ACPD‐induced Ca 2+ rises in hippocampal CA1 neurones were also antagonized (IC 50 =6.8±0.7 μ M ). LY344545 antagonized 10 μ M (S)‐3,5‐DHPG‐induced potentiation of NMDA depolarizations in CA1 neurones (EC 50 =10.6±1.0 μ M ). At higher concentrations (100 μ M ), LY344545 was an NMDA receptor antagonist. LY344545 also blocked the induction, but not the expression, of LTP at CA3 to CA1 synapses with an IC 50 >300 μ M . This effect is consistent with its weak activity at NMDA receptors. These results demonstrate that the binding of ligands to mGlu receptor subtypes is critically dependent on the spatial orientation of the same molecular substituents within a given chemical pharmacophore. The identification of LY344545 as the first competitive antagonist to show selectivity towards mGlu 5 receptors supports the potential to design more selective and potent competitive antagonists of this receptor. These results further indicate that mGlu receptor‐mediated potentiation of NMDA responses is not essential for the induction of LTP.British Journal of Pharmacology (2000) 131 , 239–244; doi: 10.1038/sj.bjp.0703574