Allosteric Modulators


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Allosteric modulation of GPCRs is rapidly emerging as a major area of interest for pharmaceutical discovery because allosteric modulators have the potential to show dramatically improved safety, tolerance, and side-effect profiles compared to traditional orthosteric agonists and antagonists. The Allosteric Modulators meeting will focus on drug development efforts for discovering and optimizing allosteric modulators of medically relevant G Protein-Coupled Receptors (GPCRs).


Allosteric Modulators of CNS Targets

1:30 pm Chairperson’s Remarks

Andrew Alt, Ph.D., Senior Research Investigator, Lead Discovery, Bristol-Myers Squibb

1:40 Development of an Amino-aza-benzimidazolone Class of mGluR2 Positive Allosteric Modulators for the Treatment of Schizophrenia

Joseph Pero, Ph.D., Associate Principal Scientist, Medicinal Chemistry, Merck

Up-regulation of glutamatergic transmission in the forebrain has been associated with the symptomology of schizophrenia. Activation of the metabotropic glutamate receptor 2 (mGluR2) regulates glutamate hyperactivity and represents a novel approach toward the treatment of the disease. Positive allosteric modulators (potentiators) of mGluR2 may offer distinct advantages over orthosteric mGluR2/3 agonists due to their unique mode of action and selectivity. This talk will describe the discovery of a novel class of azabenzimidazolone-derived mGluR2 potentiators.

2:10 Challenges and Opportunities in the Development of Muscarinic Receptor Allosteric Modulators for Schizophrenia

Christian Felder, Ph.D., Research Scientist, Neuroscience, Eli Lilly & Co.

The development of allosteric modulators and agonists is beginning to solve the pharmacological selectivity challenge for small molecule development at highly homologous receptor families. Positive allosteric modulators (PAMs) have the added benefit of providing physiologic spatial and temporal regulation of natural neurotransmitter action. Though an innovative drug development opportunity, this approach is not without its challenges. Learnings will be discussed from the development of muscarinic small molecule discovery.

2:40 Interactions of Putative Endogenous Ligands with Metabotropic Glutamate (mGlu) Receptors in the Brain

Thomas E. Salt, Ph.D., Professor, Department of Visual Neuroscience, University College of London Institute of Ophthalmology

In addition to L-glutamate, other endogenous substances (some of which belong to the kynurenine metabolism pathway) have been proposed as ligands (“endocoids”) of mGlu receptors. Disorders of these pathways could thus result in changes in mGlu receptor function contributing to pathophysiology of CNS/neurological disorders such as sensory/pain processes, cognitive processes, schizophrenia, and epilepsy. We have been investigating the interactions of such endocoids with mGlu-mediated synaptic function and allosteric modulators in vivo and in vitro.

3:10 Refreshment Break in the Exhibit Hall with Poster Viewing

Allosterism by Design


GPCR Allostery in the New Millennium: Lessons, Challenges and Opportunities

Arthur ChristopoulosArthur Christopoulos, Ph.D., Professor, Department of Pharmacology, Monash University

It is now well accepted that G protein-coupled receptors (GPCRs) possess allosteric binding sites. However, the myriad behaviors ascribed to allosteric ligands reflect not only molecular drug-receptor properties, but also cell-dependent factors that sculpt the final observed response. This presentation will focus on the minimal expectations of allosteric modulator effects and approaches for differentiating the contributions of the host system to observed allostery in order to facilitate modulator classification, structure-activity relations and translational studies.

4:45 Allosteric Modulators for Muscarinic Receptors

Andrew Tobin, Ph.D., Professor, Cell Physiology and Pharmacology, University of Leicester

5:15 Allosterism, Opioid Receptor Heteromers, and Antinociception

William P. Clarke, Ph.D., Professor, Department of Pharmacology, University of Texas Health Science Center

We present evidence, from primary cell culture and behavioral experiments, that delta and kappa opioid receptors form functional heterodimers in peripheral sensory neurons and that orthosteric ligands for one receptor of the pair allosterically regulate responses to ligands for the other receptor. Moreover, a heteromer-selective antibody against the delta-kappa heteromer also appears to allosterically regulate the response to orthosteric ligands. Some of this work has been recently published (see Berg et al, Mol Pharm 81(2):264-272, 2012).

5:45 End of Day

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