Mining the potential of label-free biosensors for seven-transmembrane receptor drug discovery.

Label-free is a broad term used to describe a number of cutting-edge biosensor technologies that have attracted considerable attention in the area of drug discovery for seven-transmembrane G protein-coupled receptors (GPCRs). Label-free biosensors resolve receptor-mediated responses noninvasively in real time and living cells and do so with high textural information and broad signaling-pathway coverage. They should facilitate studies of the receptor's integrated signal transduction biology intractable to classical assays with single pathway focus.

In vitro and in vivo characterization of the novel GABAB receptor positive allosteric modulator, 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (CMPPE).

There is preclinical evidence supporting the finding that the GABA(B) receptor orthosteric agonist, baclofen, has significant effects on eating behavior suggesting the potential therapeutic application of this compound for the treatment of eating related disorders. However, the wide clinical use of baclofen might be limited by the appearance of sedative and motor impairment effects. The identification of positive allosteric modulators (PAMs) of GABA(B) receptors represents a novel therapeutic approach to reduce the centrally-mediated adverse effects typical of the GABA(B) receptor orthosteric agonist.

The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2.

The optimisation of an HTS hit series (1) leading to the identification of structurally novel, selective, orally bioavailable mGluR2 positive modulators GSK1331258 and GSK1331268 is described. Structure-activity relationships, attenuation of dopaminergic activity, and potentiation of mGluR2 responses in rat hippocampal MPP-DG synapses are also reported.

7TM pharmacology measured by label-free: a holistic approach to cell signalling.

Ligands acting at 7-transmembrane receptors (7TMs) transduce effects on cellular behaviour in a notion termed efficacy; in turn, the cellular behaviour or phenotype can be quantified. Underpinning efficacy is the ability of ligands to dictate the triggering of distinct intracellular signalling event(s) in a system-dependent manner through selective stabilisation of receptor conformations. Given the wealth of putative cell signalling routes a receptor species may possess (spectrum of activities) and numerous mechanisms by which ligand-receptor pairings signal, the call for an integrated solution to cellular activity has come to light.

Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia.

Aberrant glutamatergic neurotransmission may underlie the pathogenesis of schizophrenia and metabotropic glutamate receptors (mGluRs) have been implicated in the disease. We have established the localization of the group III mGluR subtype, mGluR8, in the human body and investigated the biological effects of the selective mGluR8 agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG) in schizophrenia-related animal models. The mGlu8 receptor has a widespread CNS distribution with expression observed in key brain regions associated with schizophrenia pathogenesis including the hippocampus.