Structure-based discovery of positive allosteric modulators of the A adenosine receptor.

Allosteric modulation of G protein-coupled receptors (GPCRs) is an exciting strategy for developing new therapeutic agents, and it has several advantages over more commonly used orthosteric drugs. Recently determined GPCR structures have revealed allosteric pockets facing the lipid bilayer, enabling rational drug design. Here, we develop a virtual screening strategy to discover ligands of extrahelical binding pockets and apply this approach to the adenosine A receptor (AR).

Pharmacological characterisation of allosteric modulators at human mGlu.

The metabotropic glutamate receptor 5 (mGlu) is a Class C G protein-coupled receptor, ubiquitously expressed throughout the central nervous system (CNS). With major roles in cognition, learning and memory, mGlu dysfunction is linked with numerous neurodegenerative and neuropsychiatric disorders, representing a viable therapeutic target. Allosteric modulators bind topographically distinct sites from glutamate and other orthosteric agonists and enhance (positive allosteric modulators, PAMs), inhibit (negative allosteric modulators, NAMs) or do not effect (neutral allosteric ligands, NALs) mGlu function.

Pharmacology, Signaling and Therapeutic Potential of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators.

Metabotropic glutamate receptors are a family of eight class C G protein-coupled receptors regulating higher order brain functions including cognition and motion. Metabotropic glutamate receptors have thus been heavily investigated as potential drug targets for treating neurological disorders. Drug discovery efforts directed toward metabotropic glutamate receptor subtype 5 (mGlu) have been particularly fruitful, with a wealth of drug candidates and pharmacological tools identified.

Unlocking the secrets of trace amine-associated receptor 1 agonists: new horizon in neuropsychiatric treatment.

For over seven decades, dopamine receptor 2 (D receptor) antagonists remained the mainstay treatment for neuropsychiatric disorders. Although it is effective for treating hyperdopaminergic symptoms, it is often ineffective for treating negative and cognitive deficits. Trace amine-associated receptor 1 (TAAR1) is a novel, pharmacological target in the treatment of schizophrenia and other neuropsychiatric conditions.

SCA44- and SCAR13-associated GRM1 mutations affect metabotropic glutamate receptor 1 function through distinct mechanisms.

Background And Purpose: Metabotropic glutamate receptor 1 (mGlu) is a promising therapeutic target for neurodegenerative CNS disorders including spinocerebellar ataxias (SCAs). Clinical reports have identified naturally-occurring mGlu mutations in rare SCA subtypes and linked symptoms to mGlu mutations. However, how mutations alter mGlu function remains unknown, as does amenability of receptor function to pharmacological rescue.

Trace amine associated receptor 1: predicted effects of single nucleotide variants on structure-function in geographically diverse populations.

Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmaceutical target under investigation for the treatment of several neuropsychiatric conditions. TAAR1 single nucleotide variants (SNV) have been found in patients with schizophrenia and metabolic disorders. However, the frequency of variants in geographically diverse populations and the functional effects of such variants are unknown.

Rigorous Characterization of Allosteric Modulation of the Human Metabotropic Glutamate Receptor 1 Reveals Probe- and Assay-Dependent Pharmacology.

Allosteric modulation of metabotropic glutamate receptor subtype 1 (mGlu) represents a viable therapeutic target for treating numerous central nervous system disorders. Although multiple chemically distinct mGlu positive (PAMs) and negative (NAMs) allosteric modulators have been identified, drug discovery paradigms have not included rigorous pharmacological analysis. In the present study, we hypothesized that existing mGlu allosteric modulators possess unappreciated probe-dependent or biased pharmacology.

Adenosine receptor signalling in Alzheimer's disease.

Alzheimer's disease (AD) is the most common dementia in the elderly and its increasing prevalence presents treatment challenges. Despite a better understanding of the disease, the current mainstay of treatment cannot modify pathogenesis or effectively address the associated cognitive and memory deficits. Emerging evidence suggests adenosine G protein-coupled receptors (GPCRs) are promising therapeutic targets for Alzheimer's disease.

Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 as Tool Compounds to Study Signaling Bias.

Positive allosteric modulation of metabotropic glutamate subtype 5 (mGlu) receptor has emerged as a potential new therapeutic strategy for the treatment of schizophrenia and cognitive impairments. However, positive allosteric modulator (PAM) agonist activity has been associated with adverse side effects, and neurotoxicity has also been observed for pure PAMs. The structural and pharmacological basis of therapeutic versus adverse mGlu PAM in vivo effects remains unknown.

Development of Clickable Photoaffinity Ligands for Metabotropic Glutamate Receptor 2 Based on Two Positive Allosteric Modulator Chemotypes.

The metabotropic glutamate receptor 2 (mGlu) is a transmembrane-spanning class C G protein-coupled receptor that is an attractive therapeutic target for multiple psychiatric and neurological disorders. A key challenge has been deciphering the contribution of mGlu relative to other closely related mGlu receptors in mediating different physiological responses, which could be achieved through the utilization of subtype selective pharmacological tools. In this respect, allosteric modulators that recognize ligand-binding sites distinct from the endogenous neurotransmitter glutamate offer the promise of higher receptor-subtype selectivity.

Probe dependence and biased potentiation of metabotropic glutamate receptor 5 is mediated by differential ligand interactions in the common allosteric binding site.

The metabotropic glutamate receptor 5 (mGlu) is a promising therapeutic target for multiple CNS disorders. Recent mGlu drug discovery has focused on targeting binding sites within the mGlu 7-transmembrane domain (7TM) that are topographically distinct from that of the endogenous ligand. mGlu primarily couples to G proteins leading to mobilization of intracellular Ca (iCa), but also activates iCa independent signaling pathways, with biased agonism/modulation operative for multiple positive allosteric modulator (PAM) and PAM-agonist chemotypes.

Differential contribution of metabotropic glutamate receptor 5 common allosteric binding site residues to biased allosteric agonism.

Allosteric modulators of metabotropic glutamate receptor subtype 5 (mGlu) represent an attractive therapeutic strategy for multiple CNS disorders. Chemically distinct mGlu positive allosteric modulators (PAMs) that interact with a common binding site can demonstrate biased allosteric agonism relative to the orthosteric agonist, DHPG, when comparing activity in signaling assays such as IP accumulation, ERK1/2 phosphorylation (pERK1/2) and iCa mobilization. However, the structural basis for such biased agonism is not well understood.

Metabotropic glutamate receptor 5 (mGlu )-positive allosteric modulators differentially induce or potentiate desensitization of mGlu signaling in recombinant cells and neurons.

Allosteric modulators of metabotropic glutamate receptor 5 (mGlu ) are a promising therapeutic strategy for a number of neurological disorders. Multiple mGlu -positive allosteric modulator (PAM) chemotypes have been discovered that act as either pure PAMs or as PAM-agonists in recombinant and native cells. While these compounds have been tested in paradigms of receptor activation, their effects on receptor regulatory processes are largely unknown.

Identification of monellin as the first naturally derived proteinaceous allosteric agonist of metabotropic glutamate receptor 5.

Allosteric modulators bind sites distinct from orthosteric ligands, allowing for improved spatiotemporal control of receptors and greater subtype selectivity. However, we recently showed that allosteric ligands previously classified as selective for select Class C G protein-coupled receptors (GPCRs) had unappreciated activity at other off-target receptors, in some cases higher affinity, within the class. Here, we extended our investigation of off-target activity of "selective" allosteric ligands for the sweet taste receptor.

Kinetic and system bias as drivers of metabotropic glutamate receptor 5 allosteric modulator pharmacology.

Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu) have been proposed as potential therapies for various CNS disorders. These ligands bind to sites distinct from the orthosteric (or endogenous) ligand, often with improved subtype selectivity and spatio-temporal control over receptor responses. We recently revealed that mGlu allosteric agonists and positive allosteric modulators exhibit biased agonism and/or modulation.

"Selective" Class C G Protein-Coupled Receptor Modulators Are Neutral or Biased mGlu Allosteric Ligands.

Numerous positive and negative allosteric modulators (PAMs and NAMs) of class C G protein-coupled receptors (GPCRs) have been developed as valuable preclinical pharmacologic tools and therapeutic agents. Although many class C GPCR allosteric modulators have undergone subtype selectivity screening, most assay paradigms have failed to perform rigorous pharmacologic assessment. Using mGlu as a representative class C GPCR, we tested the hypothesis that allosteric modulator selectivity was based on cooperativity rather than affinity.

Pinnatoxins E, F and G target multiple nicotinic receptor subtypes.

Pinnatoxins are members of the cyclic imine group of marine phycotoxins that are highly toxic in in vivo rodent bioassays, causing rapid death due to respiratory depression. Recent studies have shown that pinnatoxins E, F and G, found in New Zealand and Australian shellfish, act as antagonists at muscle-type nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction. In the present study, binding affinities and modes of these pinnatoxin isomers at neuronal and muscle nAChRs were assessed using radioligand binding, electrophysiological and molecular modelling techniques.

In vitro labelling of muscle type nicotinic receptors using a fluorophore-conjugated pinnatoxin F derivative.

Fluorescent molecules are regularly utilised to study ligand-receptor interactions. Many ligands for nicotinic receptors have been conjugated with fluorophores to study receptor kinetics, recycling and ligand binding characteristics. These include small agonist molecules, as well as large peptidic antagonists.

Neuromuscular blocking activity of pinnatoxins E, F and G.

Pinnatoxins are produced by dinoflagellates and belong to the cyclic imine family of toxins. They are fast-acting and highly toxic when administered in vivo in rodent bioassays, causing death by respiratory depression within minutes. Studies have revealed that some cyclic imine toxins cause their toxicity by antagonizing both muscle type and heteromeric and homomeric neuronal nicotinic acetylcholine receptors (nAChRs).

Marine algal pinnatoxins E and F cause neuromuscular block in an in vitro hemidiaphragm preparation.

Members of the cyclic imine group of toxins, gymnodimine and spirolides, have been found to be potent antagonists of both muscle type and neuronal nicotinic acetylcholine receptors. These toxins exhibit fast acting toxicity in vivo, causing death within minutes by respiratory depression. This toxicity is shared by the novel cyclic imine pinnatoxins E and F, produced by marine dinoflagellates and recently isolated from New Zealand shellfish.