G protein coupled receptors as allosteric proteins and the role of allosteric modulators.

GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA.
Journal of Receptor and Signal Transduction Research (Impact Factor: 1.63). 10/2010; 30(5):313-21. DOI: 10.3109/10799893.2010.503964
Source: PubMed

ABSTRACT Seven transmembrane receptors (7TMRs) are proteins that convey signals through changes in conformation. These conformations are stabilized by external molecules (i.e. agonists, antagonists, modulators) and act upon other bodies (termed 'guests') which can be other molecules in the extracellular space, or proteins along the plane of the membrane (receptor oligomerization) or signaling proteins in the cytosol (i.e. G protein, β-arrestin). These elements comprise allosteric systems and a great deal of 7TMR pharmacology can be considered in terms of allosteric behavior. Allosteric ligands acting on 7TMRs possess four unique behaviors that can be valuable therapeutically; (1) the ability to alter the interaction of very large proteins, (2) probe dependence, (3) saturable effect, and (4) induction of separate changes in affinity and efficacy of other ligands. Two of these behaviors (namely probe dependence for CCR5-based HIV-1 entry inhibitors and functional selectivity for biased agonism) will be highlighted with examples.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The application of detailed quantitative analyses of the concentration dependence of the biological responses mediated by endogenous hormones and other mediators, drugs, and compounds, has been the foundation of pharmacology for the past century or more. This approach has been remarkably successful in identifying the specific molecular targets for these mediators and drugs, in establishing the mechanisms for those effects at both the cellular and whole organismal levels, and in the development of new chemical entities (NCEs) with great selectivity for individual molecular targets. The availability of such compounds has unfortunately led to a mindset that detailed quantitative analyses are no longer necessary to use such compounds in understanding biological system function and to draw valid conclusions in regard to the utility of NCEs selective for putative drug targets in the potential treatment of human disease states. This lack of appreciation for quantitative approaches has contrubuted significantly to the all-too-frequent failures of new drug candidates in early stage clinical trials. The present article reviews basic drug target/receptor concepts together with the mathematical relationships that underlie the quantitative analysis of dose-response and concentration-effect relationships for individual compounds and for more complex systems, such as the comparative analysis of multiple compounds at a single receptor. A thorough understanding of these concepts and their associated analyses, along with their proper and rigorous application in all pre-clinical drug development studies, is an essential component of an integrated approach toward improving drug development.
    Biochemical pharmacology 08/2013; · 4.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD and schizophrenia. Here we report two new pan-group III mGlu positive allosteric modulators, VU0155094 and VU0422288, which show differential activity at the various group III mGlus. Additionally, both compounds show probe dependence when assessed in the presence of distinct orthosteric agonists. By pairing studies of these nonselective compounds with a synapse in the hippocampus that expresses only mGlu7, we have validated activity of these compounds in a native tissue setting. These studies provide proof-of-concept evidence that mGlu7 activity can be modulated by positive allosteric modulation, paving the way for future therapeutics development.
    ACS Chemical Neuroscience 09/2014; · 3.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than do orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction.
    Neurobiology of Disease 09/2013; · 5.62 Impact Factor

Similar Publications