Lane laboratory

Dopamine receptor pharmacology

Project areas

Research focus

G  protein-coupled receptor drug discovery is characterised  by a high attrition rate, especially in the field of neuropsychopharmacology.  This reflects the difficulty in treating diseases that are complex and  polygenic in nature, such as schizophrenia. Current  antipsychotics are  predominantly efficacious at treating the positive symptoms of the disease.  However, the largely untreated negative symptoms and cognitive impairments  contribute disproportionately to the long-term disability in patients with  schizophrenia.  To address this unmet medical need novel approaches and novel  targets are required. My lab uses an integrated, multidisciplinary, approach  incorporating analytical pharmacology, structure-activity &  structure-function analyses and integrated biology to: develop novel  approaches  towards targeting the dopamine receptors; explore selective activation of the  M1 muscarinic  receptor as a novel approach towards targeting the cognitive deficits  associated with schizophrenia. Central to successfully achieving these aims is  the  exploitation of two key paradigms of GPCR drug action: allosterism  and stimulus bias.

Allosteric and bitopic targeting of dopamine receptors

Targeting  an allosteric  site on a GPCR may be associated with a number of advantages over targeting the  orthosteric  site such as improved subtype-selectivity. Although the dopamine receptors are  important drug targets allosteric  modulation  of these receptors has not been exploited therapeutically. Our  current work focuses upon:

  1. The  discovery, development and characterisation and physiological action of novel allosteric  modulators and dual orthosteric/allosteric  'bitopic'  ligands  for the dopamine D2  receptor.
  2. The  binding mode and mechanism of action of such modulators.

Stimulus bias at dopamine receptors

Aripiprazole  was developed as a low efficacy D2-selective partial agonists. However, other  D2R partial agonists show limited or no efficacy. It is possible that stimulus  bias, rather than partial agonism,  may be required to explain the efficacy of aripiprazole.  We  are currently:

  1. Exploring  the importance of biased agonism in  the action of both clinically relevant and novel drugs that target the D2R.
  2. Translating  the impact of such bias in behavioural models with predictive relevance to  symptoms of schizophrenia.
  3. Investigating  the structural determinants of biased agonism  at the D2R.

Allosteric targeting of Muscarinic M1 receptors

Muscarinic  receptor agonists have shown promise treating aspects of schizophrenia.  However, they are limited by the high  incidence of peripheral side effects associated with action at other mAChR  subtypes.

Thus the discovery of selective M1 mAChR  allosteric  modulators, such as BQCA heralds a new approach to targeting this receptor for  the treatment of cognitive deficits. We aim to:

  1. Develop  and characterise novel allosteric ligands  for the M1 mAChR.
  2. Understand  the structural basis of allostery and  bias at the M1 mAChR.
  3. Translate  parameters of allosteric  action, bias, and PK/PD to the in vivo action of such modulators in behavorial  models with predictive relevance to symptoms of schizophrenia.

back to top

Key publications

Research  papers

Shonberg  J, Klein Herenbrink  C, Lopez Munoz L, Christopoulos  A, Scammells  PJ, Capuano B, Lane JR. "A Structure-Activity Analysis of Biased Agonism  at the Dopamine D2 Receptor." (2013) J Med Chem. In Press

Lane JR, Chubukov  P, Liu W, Canals M, Cherezov V, Abagyan  R, Stevens RC, Katritch V.  "Structure-based ligand discovery targeting orthosteric  and allosteric  pockets of dopamine receptors." (2013) Mol Pharmacol.  2013 Dec;84(6):794-807.

Dror  R.O,  Green H.F., Valant C, Borhani  D.W., Valcourt  J.R., Pan A.C., Arlow D.H., Canals M., Lane J.R., Rahmani  R, Baell  J.B., Sexton P.M., Christopoulos A, Shaw D.E (2013) "Structural basis for  modulation of a G-protein-coupled  receptor by allosteric drugs" Nature In Press

McRobb  FM, Crosby IT, Yuriev E, Lane JR*,  Capuano B. "Homobivalent  ligands  of the atypical antipsychotic clozapine:  design, synthesis, and pharmacological evaluation." (2012)  J Med Chem. Feb 23;55(4):1622-34.

Lane JR*,  Klein Herenbrink  C, van Westen  GJ, Spoorendonk  JA, Hoffmann C, IJzerman AP.  A novel nonribose  agonist, LUF5834, engages residues that are distinct from those of  adenosine-like ligands to  activate  the adenosine A(2a) receptor. (2012) Mol Pharmacol.  Mar;81(3):475-87.

Canals M, Lane JR*,  Wen  A, Scammells  PJ, Sexton PM, Christopoulos A (2012) "A Monod-Wyman-Changeux mechanism can  explain G protein-coupled receptor (GPCR) allosteric modulation" J Biol Chem. 287:650-659.

Narlawar  R, Lane JR*, Doddareddy  M, Lin J, Brussee  J, Ijzerman  AP. (2010) "Hybrid ortho/allosteric  ligands  for the adenosine A(1) receptor." J Med  Chem.  53:3028-37.

Jaakola  VP, Lane JR*, Lin  JY, Katritch  V, Ijzerman  AP, Stevens RC. (2010) "Ligand binding and subtype selectivity of  the human A(2A) adenosine receptor: identification and characterization of  essential amino acid residues." J Biol  Chem. 285:13032-13044.

Jaakola  VP, Griffith MT, Hanson MA, Cherezov  V, Chien  EY, Lane JR, Ijzerman  AP, Stevens RC. (2008) "The 2.6 angstrom crystal structure of a human A2A  adenosine receptor bound to an antagonist." Science.  322:1211-1217.

Lane JR,  Powney  B, Wise A, Rees S, Milligan G. (2007) Protean agonism  at the dopamine D2 receptor: (S)-3-(3-hydroxyphenyl)-N-propylpiperidine is an  agonist for activation of Go1 but an antagonist/inverse agonist for Gi1,Gi2,  and Gi3. Mol  Pharmacol. 71:1349-1259.

Reviews

Lane JR, Abdul-Ridha  A, Canals M (2013) "Regulation of G protein-coupled receptors by allosteric  ligands" ACS Chem Neurosci  4:527-534.

Lane JR,  Canals M (2012) "Sequential conformational rearrangements dictate the dynamics  of family C GPCR activation"   Sci  Signaling 5(251): pe51

Lane JR,  Sexton PM, Christopoulos  A. (2013) "Bridging the gap: bitopic  ligands  of G-protein-coupled receptors."  Trends Pharmacol Sci. 34:59-66.

Valant  C, Lane JR*,  Sexton PM, Christopoulos  A. (2012) "The best of both worlds? Bitopic  orthosteric/allosteric  ligands  of G protein-coupled receptors." Annu Rev Pharmacol Toxicol. 52:153-78.

Milligan G, Parenty  G, Stoddart  LA, Lane JR. (2007)  "Novel pharmacological applications of G-protein-coupled receptor-G protein  fusions." Curr Opin Pharmacol.  7:521-6.

*  denotes corresponding author.

back to top

Collaborations

Monash  Institute of Pharmaceutical Sciences:

Monash  University (Clayton)

  • Dr. Oded Kleinfeld -  Proteomic approaches to investigate GPCR biased-agonism

External  collaborations

  • Prof. Jonathan Jatvitch (Columbia University, New York) – allosteric  modulation and stimuus bias  at the dopamine D2 receptor
  • Ass.  Prof. Le Shi (Weill Medical College of Cornell  University  )  – allosteric  modulation and stimulus bias at the dopamine D2 receptor
  • Ass.  Prof. Seva Katrich (Scripps Institute, La Jola)  – allosteric  targeting of dopamine D2 receptors
  • Prof. Nevin Lambert  (University of Georgia) - BRET approaches to study receptor trafficking
  • Dr. Martyn Wood (UCB)  -  allosteric modulation of dopamine receptors

back to top

Lab members

Dr Holly Yeatman
Postdoctoral fellow

Dr Herman Lim
Postdoctoral fellow

Chris Draper-Joyce
PhD candidate

Carmen Klein-Herenbrink
PhD candidate

Monika Szabo
PhD candidate

Dr Ann Stewart
Research Assistant

back to top

Funding

  • Larkins Fellowship (Monash University) (2010 –  2013)
  • R.D.  Wright NHMRC Career Development Fellowship (2013-2017)
  • VENI  Fellowship (2010-2013) (NWO, The Netherlands)
  • NHMRC  Project Grant (2012 – 2015) Rational  Co-targeting of G protein-coupled receptors as a novel approach towards  treating neuropsychiatric  disorders (CIA)
  • NHMRC  Project Grant (2011 – 2014) Bitopic  ligands  as a novel approach to G protein-coupled receptor selectivity (CIA)

back to top