Most drugs function by binding to receptors, with notable exceptions including antibiotics and anesthetics. The four major classes of receptors are:

  • G protein-coupled receptors (GPCRs)
  • Ion-channel receptors
  • Tyrosine kinase-linked receptors
  • Receptors that possess intrinsic enzymatic activity

The G protein-coupled receptors (GPCRs) are a superfamily of proteins accounting for approximately 1% of the human genome. When the first sequences of GPCRs became available in the mid-1980s, including rhodopsin, muscarinic, and adrenergic receptors, the sequence homology among receptors involved in diverse signaling systems was revealed. We now appreciate that GPCRs constitute a family, with variable external conformations to accommodate different ligands and somewhat less variable intracellular configurations required for G protein-coupling. The extracellular subunit serves as the binding site for natural or synthetic substances, while the intracellular subunit serves as a scaffold for a cascade of signaling events, including the activation of second messengers and cellular responses, as well as the deactivation or desensitization processes. The class is also characterized by seven well-conserved membrane-spanning subunits which anchor the receptor to the cell membrane and give rise to the name “heptahelical” receptors.

GPCRs regulate an enormous range of physiological processes, including hormonal control of virtually all physiological functions; many instances of synaptic neurotransmission; the perception of light, taste, smell and pain; the attraction of motile cells by chemotaxis; the stimulation and regulation of mitosis (cell division); and even the entry of viruses such as HIV into cells. In addition to dramatically increasing our understanding of the molecular basis of human physiology and pathology, the GPCRs whose natural ligands and functions have been elicited to date (i.e., known GPCRs) have been the most fruitful targets in history for drug discovery and therapeutic intervention.

Known GPCRs

Today, there are nearly 200 GPCRs whose natural ligands and function are known. These known GPCRs, named for their endogenous ligands, have been classified into five major categories: 

  • Class-A Rhodopsin-like
  • Class-B Secretin-like
  • Class-C Metabotropic glutamate/pheromone
  • Class-D Fungal pheromone
  • Class-E cAMP (dictyostelium)

Representative members of Class-A are the amine receptors (e.g., muscarinic, nicotinic, adrenergic, adenosine, dopamine, histamine and serotonin), the peptide receptors (e.g., angiotensin, bradykinin, chemokines, endothelin and opioid), the hormone receptors (e.g., follicle stimulating, lutropin and thyrotropin), and the sensory receptors, including rhodopsin (light), olfactory (smell) and gustatory (taste) receptors. Representatives of Class-B include secretin, calcitonin, gastrin and glucagon receptors. Much less is known about Classes C-E.

In addition to a wide variety of GPCRs within a class, allowing for the regulation of a wide variety of physiologies, many GPCRs are themselves a family of receptors with various subtypes. For example, there are six different a- and three different b-adrenergic receptor subtypes, five dopamine, four adenosine, four histamine and 16 different serotonin receptor subtypes. These subtypes allow for further discrimination of cellular response based on tissue distribution or expression levels, and in some cases provide for negative-feedback regulation or inhibition.

GPCR-Based Drugs

Examples of commonly prescribed GPCR-based drugs are:

  • Atenolol (Tenormin®); b1-adrenergic antagonist - AstraZeneca
  • Albuterol (Ventolin®); b2-adrenergic agonist - GlaxoSmithKline
  • Ranitidine (Zantac®); H2-histamine antagonist - GlaxoSmithKline
  • Loratadine (Claritin®); H1-histamine antagonist - Schering Corporation
  • Hydrocodone (Vicodin®); m-opioid agonist - Knoll Pharmaceutical Company
  • Theophylline (TheoDur®); adenosine antagonist - Key Pharmaceuticals
  • Fluoxetine (Prozac®); indirect-acting serotonin agonist - Eli Lilly and Company

Despite a wide variety of marketed GPCR-based drugs, the functionally known receptors remain important targets for new and improved drugs. Greater selectivity for a particular receptor subtype could provide more specific activity and fewer side effects. A direct-acting serotonin (5-HT) receptor subtype agonist, for example, could represent a major improvement over Prozac®. However, it is not yet known which of the 16 different 5-HT receptor subtypes are primarily responsible for imparting the anti-depressant effects of the drug. Moreover, characterizing the functional differences between these subtypes would require a collection of highly selective ligands in the first instance. Regardless, the known GPCRs have been and will remain important targets for drug discovery.

Due to the overwhelming variety of physiologies regulated, GPCRs have been the richest targets in history for drug discovery. It is estimated that nearly 60% of all prescription drugs on the market owe their activity in whole or in part to GPCRs. While some of the natural ligands have important therapeutic value (e.g., epinephrine, dopamine and adenosine), most are synthetic ligands or derivatives that bind and either activate or block the receptor, so-called agonists and antagonists, respectively. Many compounds have pure stimulatory or inhibitory properties, while others are a mixed breed, including partial agonists or antagonists, inverse agonists, and allosteric modulators. In addition to these direct-acting drugs, others act indirectly on GPCRs by promoting or inhibiting the cellular synthesis, release or reuptake of the natural ligand.

Orphan GPCRs

In the past, endogenous ligands were used to isolate GPCRs through demanding techniques such as protein purification and expression cloning. Cloning by sequence homology identified the major genes encoding GPCRs with known endogenous ligands. This growing database is now in the public domain and accessible through the internet at This shift from ligand-based to sequence-based receptor discovery facilitated the identification of many receptors and their subtypes. In addition, sequence-based discovery unveiled a host of novel receptors for which the endogenous ligands are not yet known. These are the “orphan” GPCRs, which are similar to a variety of different GPCR subfamilies.
If history is any indication, orphan GPCRs are a target-rich environment for drug discovery. Completion of the Human Genome Project now suggests that there are over 1,000 orphan GPCRs which, depending upon their function, hold great promise to refill the pharma pipeline with blockbuster therapeutics. In addition, arguably the largest subclass of orphans is the more than 300 human sensory receptors, themselves having enormous potential in the food, beverage, and cosmetics industries.

Of course, key to the value of any given orphan GPCR is an understanding of the physiology it regulates. Unfortunately, without its natural ligand, a synthetic ligand, or some other method of initiating receptor activation, it is difficult and time consuming to “functionalize” or “deorphanize” a GPCR. Despite the many tools available to the modern molecular biologist, very few GPCRs have been “deorphanized” in this post-sequencing era.

Recently Discovered GPCR Ligands