November 15, 2008 (Vol. 28, No. 20)

Technologic and Scientific Advances Spark Expansion of the Repertoire of GPCR-Targeted Drugs

The differences in targets between launched and developmental compounds addressing GPCRs reflect a sea change in the pharmaceutical research paradigm. Technologic and scientific advances in recent years have resulted in R&D pipelines that target a great many more GPCRs than are represented among currently marketed products. Indeed, 91 GPCRs are currently the subject of compounds in preclinical development alone, compared with the 46 GPCRs that are targeted by launched drugs.

GPCRs, or G protein-coupled receptors, account for approximately one-third of all approved drugs. Yet one can easily argue that the pharmacologic potential of this extremely popular target class is far from exhausted. Despite the large number of GPCRs that are available as targets, most currently approved drugs address those that are activated by biogenic amines. A key reason for this limitation is that early high-throughput screening efforts were based largely on competitive ligand-binding assays, for which the biogenic amines were highly amenable.

GPCR-based drug discovery has come a long way since these first-generation drugs made it through the pipeline. Advances in medicinal chemistry and structure-based drug design have made possible large increases in the number and diversity of targets for which compounds are currently in development. Perhaps even more importantly, over the last decade, screening technologies have evolved from mainly measuring binding to elucidating a variety of functional parameters, which has opened the door to working with a great many more receptors than were previously accessible.

Of 371 known nonsensory GPCR types and subtypes, 125 are targeted by compounds on the market or in development. Only a few of these targeted receptors are still in orphan status (i.e., their endogenous ligands have not yet been identified), although 100–150 receptors relevant to drug discovery remain orphans, which suggests that there is a great deal of valuable territory yet to explore. One challenge for the next decade will be identifying ligands for these receptors and translating them into drug targets.

Allosteric Modulation

The evolution of GPCR pharmacology is far from over. Researchers have made a number of exciting and relevant discoveries in the past decade, and these have already begun to make important contributions to GPCR drug discovery.

No single topic in the GPCR world, however, currently generates more justified excitement than allosteric modulation, which has already yielded two marketed drugs and promises many more, some with capabilities, that have been so far, inaccessible. Because they do not compete with GPCRs’ natural ligands, allosteric modulators have the potential to be effective at lower, safer doses vis-à-vis orthosteric modulators. Allosteric modulators have already been identified for 34 GPCR types and subtypes. In the next seven or eight years, we may see that the majority of novel GPCR-targeted drugs act via allosteric modulation as opposed to orthosteric.

There is one research advance which has, arguably, the greatest potential for advancing GPCR pharmacology. Until last year, drug discovery scientists had available to them only a single, high-resolution x-ray crystallographic structure of a GPCR, rhodopsin, which is atypical from a drug discovery perspective.

Barriers have now been broken, and two GPCR structures, with characteristics placing them in the mainstream of commercial pharmacology interest, have become available. This confers the ability to rationally target GPCRs as opposed to running random high-throughput screens to design molecules—a development that has heralded a new era in GPCR structure-based drug design.

Drug Discovery Outlook

The GPCR field can fairly be described as vibrant and dynamic with great promise of exciting new applications to come. A number of small pharmaceutical companies are pushing the limits of GPCR pharmacology by attacking more new targets and attempting to apply cutting-edge concepts derived from basic research such as multimerization and functional selectivity, both of which promise to have significant impact on the field.

Many such smaller companies have entered into lucrative agreements with big pharma. Addex Pharmaceuticals has two agreements with Merck & Co. that are centered on development of allosteric modulators—one of these deals is worth up to $702 million. GlaxoSmithKline has struck agreements with Actelion and Epix Pharmaceuticals, worth up to about $3 billion and $1.5 billion, respectively.

Because GPCRs have been the most successful of any drug target class, it would be a reasonable perception that much of the low-hanging fruit has been picked. But in fact, doors continue to open, illuminating new pathways for GPCR drug discovery.

“There are so many opportunities we never envisioned five years ago such as heterodimers, functional selectivity, and the whole area of allosteric modulators in general. I believe that the opportunities we have now are tremendous and unprecedented,” said P. Jeffrey Conn, Ph.D., director of drug discovery at Vanderbilt University.

Crystal structure of the beta2-adrenergic receptor protein

Ken Rubenstein, Ph.D., is the author of “GPCRs: Dawn of a New Era?” This report is available from Insight Pharma Reports, a division of Cambridge Healthtech Institute. Web:

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