Bridging the gap: bitopic ligands of G-protein-coupled receptors.

Although classical approaches to G-protein-coupled receptor (GPCR) drug design have targeted the orthosteric binding site, potentially all GPCRs possess druggable allosteric sites. In addition, it is clear that GPCRs can adopt multiple active states linked to distinct functional outcomes that can be stabilized by both allosteric and orthosteric ligands. Recent studies have begun to explore the possibilities of linking orthosteric and allosteric pharmacophores to yield 'bitopic' ligands as an approach to achieve improved receptor affinity or selectivity. Furthermore, it is possible that previously identified functionally selective drugs may represent unappreciated bitopic ligands at this important class of drug targets. Here we discuss both the potential of bitopic ligands in GPCR drug discovery and the challenges associated with the design of such ligands.

[1]  J. Massagué.  TGF-beta signal transduction. , 1998, Annual review of biochemistry.

[2]  P. Scammells,et al.  Design Strategies for Bivalent Ligands Targeting GPCRs , 2011, ChemMedChem.

[3]  U. Holzgrabe,et al.  Allosteric ligands for G protein‐coupled receptors: A novel strategy with attractive therapeutic opportunities , 2010, Medicinal research reviews.

[4]  P. Sexton,et al.  Allosteric Ligands of the Glucagon-Like Peptide 1 Receptor (GLP-1R) Differentially Modulate Endogenous and Exogenous Peptide Responses in a Pathway-Selective Manner: Implications for Drug Screening , 2010, Molecular Pharmacology.

[5]  R. Abagyan,et al.  Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists , 2010, Science.

[6]  Edgar Jacoby,et al.  The 7 TM G‐Protein‐Coupled Receptor Target Family , 2006, ChemMedChem.

[7]  Brian K. Shoichet,et al.  Structure-Based Discovery of A2A Adenosine Receptor Ligands , 2010, Journal of medicinal chemistry.

[8]  Peter Kolb,et al.  Structure-based discovery of β2-adrenergic receptor ligands , 2009, Proceedings of the National Academy of Sciences.

[9]  Arthur Christopoulos,et al.  Orthosteric/allosteric bitopic ligands: going hybrid at GPCRs. , 2009, Molecular interventions.

[10]  J. Andrew McCammon,et al.  Mapping the Druggable Allosteric Space of G-Protein Coupled Receptors: a Fragment-Based Molecular Dynamics Approach , 2010, Chemical biology & drug design.

[11]  Arthur Christopoulos,et al.  Identification of Orthosteric and Allosteric Site Mutations in M2 Muscarinic Acetylcholine Receptors That Contribute to Ligand-selective Signaling Bias* , 2010, The Journal of Biological Chemistry.

[12]  M. Brann,et al.  Identification of a Ligand-dependent Switch within a Muscarinic Receptor* , 1998, The Journal of Biological Chemistry.

[13]  Jonathan A. Javitch,et al.  Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist , 2010, Science.

[14]  Jonathan S. Mason,et al.  Progress in Structure Based Drug Design for G Protein-Coupled Receptors , 2011, Journal of medicinal chemistry.

[15]  Judy Lin,et al.  Hybrid ortho/allosteric ligands for the adenosine A(1) receptor. , 2010, Journal of medicinal chemistry.

[16]  A. Deutch,et al.  Novel Selective Allosteric Activator of the M1 Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats , 2008, The Journal of Neuroscience.

[17]  Evi Kostenis,et al.  An optical dynamic mass redistribution assay reveals biased signaling of dualsteric GPCR activators , 2009, Journal of receptor and signal transduction research.

[18]  P. Sexton,et al.  Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology. , 2007, Trends in pharmacological sciences.

[19]  Vadim Cherezov,et al.  Diversity and modularity of G protein-coupled receptor structures. , 2012, Trends in pharmacological sciences.

[20]  S. Rasmussen,et al.  Crystal Structure of the β2Adrenergic Receptor-Gs protein complex , 2011, Nature.

[21]  U. Holzgrabe,et al.  Design, synthesis, and action of oxotremorine-related hybrid-type allosteric modulators of muscarinic acetylcholine receptors. , 2006, Journal of medicinal chemistry.

[22]  Albert C. Pan,et al.  Pathway and mechanism of drug binding to G-protein-coupled receptors , 2011, Proceedings of the National Academy of Sciences.

[23]  A. Kruse,et al.  Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist , 2011, Nature.

[24]  U. Holzgrabe,et al.  Rational design of dualsteric GPCR ligands: quests and promise , 2010, British journal of pharmacology.

[25]  R. Nussinov,et al.  Dynamic allostery: linkers are not merely flexible. , 2011, Structure.

[26]  Arthur Christopoulos,et al.  Allosteric modulation of G protein-coupled receptors. , 2007, Annual review of pharmacology and toxicology.

[27]  Christopher J Langmead,et al.  Mutagenic Mapping Suggests a Novel Binding Mode for Selective Agonists of M1 Muscarinic Acetylcholine Receptors , 2009, Molecular Pharmacology.

[28]  Arthur Christopoulos,et al.  A Novel Mechanism of G Protein-coupled Receptor Functional Selectivity , 2008, Journal of Biological Chemistry.

[29]  U. Holzgrabe,et al.  Dualsteric GPCR targeting: a novel route to binding and signaling pathway selectivity , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  M. Jacobson,et al.  The M1 Muscarinic Receptor Allosteric Agonists AC-42 and 1-[1′-(2-Methylbenzyl)-1,4′-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one Bind to a Unique Site Distinct from the Acetylcholine Orthosteric Site , 2010, Molecular Pharmacology.

[31]  R. Stevens,et al.  High-Resolution Crystal Structure of an Engineered Human β2-Adrenergic G Protein–Coupled Receptor , 2007, Science.

[32]  R. Stevens,et al.  The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist , 2008, Science.

[33]  Arthur Christopoulos,et al.  A simple method for quantifying functional selectivity and agonist bias. , 2012, ACS chemical neuroscience.

[34]  M. Mammen,et al.  A Novel Multivalent Ligand That Bridges the Allosteric and Orthosteric Binding Sites of the M2 Muscarinic Receptor , 2007, Molecular Pharmacology.

[35]  P. Sexton,et al.  The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors. , 2012, Annual review of pharmacology and toxicology.

[36]  Avner Schlessinger,et al.  Ligand Discovery from a Dopamine D3 Receptor Homology Model and Crystal Structure , 2011, Nature chemical biology.

[37]  L. Pardo,et al.  Crystal structure of the μ-opioid receptor bound to a morphinan antagonist , 2012, Nature.

[38]  T. Schwartz,et al.  Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act? , 2007, Trends in pharmacological sciences.

[39]  George M Whitesides,et al.  Polyvalent Interactions in Biological Systems: Implications for Design and Use of Multivalent Ligands and Inhibitors. , 1998, Angewandte Chemie.

[40]  Ruben Abagyan,et al.  Structure of the human histamine H1 receptor complex with doxepin , 2011, Nature.

[41]  Xavier Deupi,et al.  Conformational complexity of G-protein-coupled receptors. , 2007, Trends in pharmacological sciences.

[42]  Aashish Manglik,et al.  Structure of the δ-opioid receptor bound to naltrindole , 2012, Nature.

[43]  M. Whittington,et al.  Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77‐LH‐28‐1 , 2008, British journal of pharmacology.

[44]  C. Langmead,et al.  Probing the Molecular Mechanism of Interaction between 4-n-Butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine (AC-42) and the Muscarinic M1 Receptor: Direct Pharmacological Evidence That AC-42 Is an Allosteric Agonist , 2006, Molecular Pharmacology.

[45]  A. Christopoulos,et al.  Ligand functional selectivity and quantitative pharmacology at G protein-coupled receptors , 2011, Expert opinion on drug discovery.

[46]  Arthur Christopoulos,et al.  Orthosteric and Allosteric Modes of Interaction of Novel Selective Agonists of the M1 Muscarinic Acetylcholine Receptor , 2010, Molecular Pharmacology.

[47]  Laurence J. Miller,et al.  Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery , 2010, Pharmacological Reviews.

[48]  Richard Morphy,et al.  From magic bullets to designed multiple ligands. , 2004, Drug discovery today.

[49]  P. Portoghese,et al.  From models to molecules: opioid receptor dimers, bivalent ligands, and selective opioid receptor probes. , 2001, Journal of medicinal chemistry.

[50]  Jaroslav Koca,et al.  CAVER: a new tool to explore routes from protein clefts, pockets and cavities , 2006, BMC Bioinformatics.

[51]  Bryan L. Roth,et al.  Structure of the human kappa opioid receptor in complex with JDTic , 2012, Nature.

[52]  M. Mammen,et al.  THRX-198321 Is a Bifunctional Muscarinic Receptor Antagonist and β2-Adrenoceptor Agonist (MABA) That Binds in a Bimodal and Multivalent Manner , 2011, Molecular Pharmacology.

[53]  K. Wreggett,et al.  An Intracellular Allosteric Site for a Specific Class of Antagonists of the CC Chemokine G Protein-Coupled Receptors CCR4 and CCR5 , 2008, Molecular Pharmacology.

[54]  K. Gregory,et al.  Allosteric Modulation of Muscarinic Acetylcholine Receptors , 2007, Current neuropharmacology.

[55]  P. Sexton,et al.  Molecular Mechanisms of Action and In Vivo Validation of an M4 Muscarinic Acetylcholine Receptor Allosteric Modulator with Potential Antipsychotic Properties , 2010, Neuropsychopharmacology.