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Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders
There have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function that provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.
A Novel Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Has in Vivo Activity and Antipsychotic-Like Effects in Rat Behavioral Models
It is demonstrated that positive allosteric modulation of mGluR5 produces behavioral effects, suggesting that such modulation serves as a viable approach to increasing mGLUR5 activity in vivo.
In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors.
It is shown that dorsomorphin has significant "off-target" effects against the VEGF (vascular endothelial growth factor) type-2 receptor (Flk1/KDR) and disrupts zebrafish angiogenesis, demonstrating the potential of zebra fish as an attractive complementary platform for drug development that incorporates an assessment of in vivo bioactivity and selectivity in the context of a living organism.
Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors.
An iterative analog library synthesis approach quickly provided a highly selective Akt1/Akt2 inhibitor that induces apoptosis in tumor cells and inhibits Akt phosphorylation in vivo.
Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.
The power of diversity-oriented synthesis combined with biochemical assays and mass spectrometric lipid profiling of cellular responses to develop the first isoform-selective PLD inhibitors--a new class of antimetastatic agents is demonstrated.
Phospholipase D: enzymology, functionality, and chemical modulation.
In this comprehensive review of the PLD superfamily, specific emphasis is given to the conventional mammalian isoforms, PLD1 and PLD2, and the tools with which these enzymes are studied.
Small-molecule screen identifies inhibitors of the neuronal K-Cl cotransporter KCC2
A fluorescence-based assay suitable for high-throughput screening (HTS) and a large number of molecules that either decrease or increase the activity of the cotransporter are identified, some of which inhibit KCC2 activity in the submicomolar range without substantially affecting NKCC1 activity.
Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia.
Animal studies suggest that mGluR5 agonists could provide a novel approach for the treatment of all major symptom domains of schizophrenia and have robust effects in animal models that predict efficacy in treatment of schizophrenia.
Identification of ML204, a Novel Potent Antagonist That Selectively Modulates Native TRPC4/C5 Ion Channels*
In isolated guinea pig ileal myocytes, ML204 blocked muscarinic cation currents activated by bath application of carbachol or intracellular infusion of GTPγS, demonstrating its effectiveness on native TRPC4 currents.
Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation
  • Lei Ma, M. Seager, +25 authors W. Ray
  • Biology, Medicine
    Proceedings of the National Academy of Sciences
  • 15 September 2009
Benzyl quinolone carboxylic acid exploits an allosteric potentiation mechanism to provide selectivity for the M1 receptor and represents a promising therapeutic strategy for cognitive disorders.