Dopamine receptor pharmacology
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:
- The discovery, development and characterisation and physiological action of novel allosteric modulators and dual orthosteric/allosteric 'bitopic' ligands for the dopamine D2 receptor.
- 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:
- Exploring the importance of biased agonism in the action of both clinically relevant and novel drugs that target the D2R.
- Translating the impact of such bias in behavioural models with predictive relevance to symptoms of schizophrenia.
- 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:
- Develop and characterise novel allosteric ligands for the M1 mAChR.
- Understand the structural basis of allostery and bias at the M1 mAChR.
- 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.
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.
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.
Monash Institute of Pharmaceutical Sciences:
- Prof. Arthur Christopoulos - Allosteric Targeting of Muscarinic M1 receptors
- Dr Michelle Halls - Signalling dynamics of dopamine receptors
- Dr Meritxell Canals- Regulation and trafficking of the dopamine D2 receptor
- Dr Erica Sloan- Adrenergic receptor signalling in breast cancer
- Dr Ben Capuano – Synthesis of novel D2R ligands
- Prof. Peter Scammells - Synthesis of novel M1 muscarinic receptor modulators
- Dr. David Shackleford- Allosteric Targeting of Muscarinic M1 receptors
Monash University (Clayton)
- Dr. Oded Kleinfeld - Proteomic approaches to investigate GPCR biased-agonism
- 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
Dr Holly Yeatman
Dr Herman Lim
Dr Ann Stewart
- 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)