Discovery of BI-9508, a Brain-Penetrant GPR88-Receptor-Agonist Tool Compound for Mouse Studies.

Decreased activity and expression of the G-protein coupled receptor GPR88 is linked to many behavior-linked neurological disorders. Published preclinical GPR88 allosteric agonists all have pharmacokinetic properties that preclude their progression to the clinic, including high lipophilicity and poor brain penetration. Here, we describe our attempts to improve GPR88 agonists' drug-like properties and our analysis of the trade-offs required to successfully target GPR88's allosteric pocket.

GPCR Binding Technologies: An Overview.

With the apparition of concepts such as allosteric modulation and functional selectivity the field of G-protein coupled receptors drug discovery has regained its momentum. To better address this paradigm shift new screening technologies were developed. To identify novel GPCR ligands the screening method of choice was based upon functional assay for the last decade and is now being complemented by several innovative binding technologies.

Chemical switch of a metabotropic glutamate receptor 2 silent allosteric modulator into dual metabotropic glutamate receptor 2/3 negative/positive allosteric modulators.

Using an mGluR2 FRET-based binding assay, binders of the transmembrane region devoid of functional activity were identified. It is reported that slight chemical modifications of these SAMs can dramatically change activity of the resulting analogues without altering their affinities. Starting from compound 1, three mGluR2 NAMs showing also mGluR3 PAM activities were obtained.

Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist.

Apelin plays a prominent role in body fluid and cardiovascular homeostasis. To explore further upstream the role played by this peptide, nonpeptidic agonists and antagonists of the apelin receptor are required. To identify such compounds that do not exist to date, we used an original fluorescence resonance energy transfer-based assay to screen a G-protein-coupled receptor-focused library of fluorescent compounds on the human EGFP-tagged apelin receptor.

Small neutralizing molecules to inhibit actions of the chemokine CXCL12.

The chemokine CXCL12 and the receptor CXCR4 play pivotal roles in normal vascular and neuronal development, in inflammatory responses, and in infectious diseases and cancer. For instance, CXCL12 has been shown to mediate human immunodeficiency virus-induced neurotoxicity, proliferative retinopathy and chronic inflammation, whereas its receptor CXCR4 is involved in human immunodeficiency virus infection, cancer metastasis and in the rare disease known as the warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome. As we screened chemical libraries to find inhibitors of the interaction between CXCL12 and the receptor CXCR4, we identified synthetic compounds from the family of chalcones that reduce binding of CXCL12 to CXCR4, inhibit calcium responses mediated by the receptor, and prevent CXCR4 internalization in response to CXCL12.