GPCR Molecular Pharmacology and Drug Targeting Shifting Paradigms and New Directions

by Gilchrist, Annette

• ISBN13: 9780470307786
• ISBN10: 0470307781
• Edition: 1st
• Format: Hardcover
• Copyright: 2010-08-09
• Publisher: Wiley

Summary

G protein-coupled receptors (GPCRs) are a large protein family of transmembrane receptors vital in dictating cellular responses. GPCRs are involved in many diseases, but are also the target of around half of all modern medicinal drugs. Shifting Paradigms in G Protein Coupled Receptors takes a look at the way GPCRs are examined today, how they react, how their mutations lead to disease, and the many ways in which they can be screened for compounds that modulate them. Chemists, pharmacologists, and biologists will find essential information in this comprehensive reference.

Author Biography

Annette Gilchrist, PhD, is Assistant Professor of Pharmaceutical Sciences at Midwestern Univeristy’s Chicago of Pharmacy, and Adjunct Professor at Northwestern University in the Department of Molecular Pharmacology and Biological Chemistry. Previously, she cofounded and was chief scientific officer for Caden Biosciences, and cofounded and was president of Cue BIOtech, companies committed to GPCR discovery efforts. A life sciences industry consultant and regular speaker at ACS, SBS, DIA, BIO, and CHI conferences, she has twenty-four peer-reviewed publications and four issued patents.

Table of Contents

The Evolution of Receptors: From On-Off Switches to Micro-Processors

Introduction

The Receptor as an On-Off Switch

Historical background and Classical Receptor Theory

The Operational Model of Drug Action

Receptor Antagonism

Specific Models of GPCRs (7TM receptors)

The Receptor as Microprocessor: Ternary Complex Models

Receptors as Basic Drug Recognition Units

Receptor Structure

Future Considerations

The Evolving Pharmacology of GPCRs

Agonists, neutral antagonists and inverse agonists

LDTRS/protean agonism

Molecular mechanisms of GPCR ligand binding

Two GPCR ligands binding at once- concept of allosterism

GPCR dimerisation

Future Perspectives

The Emergence of Allosteric Modulators for G Protein-Coupled Receptors

Introduction

Foundations of Allosteric Receptor Theory

Models for Understanding the Effects of Allosteric Modulators

Types of Allosteric Modulators and Their Properties

Detection and Quantification of Allosteric Interactions

Some Examples of GPCR Allosteric Modulators

Concluding Remarks

Receptor-mediated G protein activation: how, how many and where?

The mechanical problem - three different solutions

Receptor monomers - dimers - oligomers: one size fits all?

Corrals, fences, rafts - are there privileged places for GPCR activation?

Molecular Pharmacology of Frizzleds - with implications for possible therapy

Introduction

Frizzleds as WNT receptors

Frizzled signaling

Frizzleds? physiology & possible therapy

Secretin receptor dimerization: A possible functionally-important paradigm for Family B G protein-coupled receptors

Methodological approaches to GPCR oligomerization

Structural themes for GPCR oligomerization

Functional effects of GPCR oligomerization

Secretin receptor oligomerization

Past and Future Strategies for GPCR Deorphanization

Introduction

Current strategies to identify the ligand and function of orphan 7TM proteins

Functional assays for deorphanization

Future directions and new concepts

Controversial issues

High throughput GPCR screening technologies and the emerging importance of the cell phenotype

Introduction

How are GPCR drugs discovered?

GPCR dependence on G proteins

Technologies for GPCR compound screening and drug discovery

Importance of Target cells in GPCR HTS assays

Are "traditional" biochemical techniques out of fashion in the new era of GPCR pharmacology?

Overview

Receptor Binding Assays

Methods for Measurement of cAMP

Conclusions

Fluorescence and resonance energy transfer shine new light on GPCR function

Overview

Introduction

Labeling GPCRs with fluorescent tags

Detection of fluorescence and bioluminescence

Fluorescence-based assays to study receptor localization, trafficking and receptor function

Resonance energy transfer, a tool to get new insights into GPCR function

Analysis of steady state protein/protein interaction by means of RET

Kinetic analysis of protein/protein interactions by means of FRET

Detection of receptor function by fluorescence resonance energy

Integration of label-free detection methods in GPCR drug discovery

Overview

Introduction

Label free technologies -- past and present

A. Automated microscopes and microbalances

Discussion

Screening for allosteric modulators of G protein-coupled receptors

Introduction

The allosteric ternary complex model (ATCM), radioligand binding and affinity

Beyond affinity - functional assays, efficacy and allosteric agonism

Allosteric modulator titration curves

The impact of functional assay format on allosteric modulator screening

Taking advantage of structural understanding of allosteric binding sites

Summary and future directions

Ultra High Throughput Screening Assays for GPCRs

Introduction

Assay Types for GPCRs in uHTS

Summary

New techniques to express and crystallise G protein coupled receptors

Introduction

Key problems limiting production of 3D GPCR structures

History of GPCR structures

The search for other GPCR structures

Protein purification and solubilisation

In cubo crystallisation

Engineering receptor stability

Structures of the ß2 adrenergic receptor

The adenosine A2a receptor

Conclusions and Future developments

Structure and Modeling of GPCRs: Implications for drug discovery

Introduction

High resolution GPCR modeling

Constructing and Evaluating Homology Models of Other Receptor Types

Modeling GPCR Functional Features - Analysis of activation and signaling

Beyond Class A: modeling of other GPCR families

Summary and Conclusions

X-ray Structure Developments for GPCR Drug Targets

Overview

Introduction

Class A GPCRs

Class C GPCRs

Conclusions

Pharmacological Chaperones: Potential for the Treatment of Hereditary Diseases Caused by Mutations in G Protein-coupled Receptors

Overview

Introduction

Nephrogenic Diabetes Insipidus and the Vasopressin V2 Receptor

Retinitis Pigmentosa and the Rhodopsin Receptor

Idiopathic Hypogonadotropic Hypogonadism and the Gonadotropin-Releasing Hormone Receptor

Other Human Diseases Caused by Inactivating Mutations in GPCRs

Considerations for the Therapeutic Use of Pharmacological Chaperones

Concluding Remarks

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