The Molecular Pharmacology of G-Protein Coupled Receptors
Research
The research focus of the Molecular Pharmacology laboratory is activation and regulation of members of the G-Protein Coupled Receptors (GPCR) superfamily.
GPCRs
GPCR are of fundamental importance in cell signalling, and thus are important drug targets.
The G-protein-coupled receptor (GPCR) superfamily is a large protein family, accounting for ~5% of the human genome, and is the target for ~50% of all pharmaceutical compounds. This superfamily of receptors is involved in the regulation of every physiological system and has ligands that cover a diverse range of compounds from photons to proteins. These ligands interact with the extracellular loops and upper portion of the transmembrane helix bundle of GPCRs, leading to conformational changes in the lower portion of the helices, and the intracellular loops and tail domains, resulting in receptor interaction with signalling proteins.
GPCR Structure and Function
Structural evidence of the molecular mechanisms that leads to GPCR activation is very limited. Research in our laboratory will contribute to the better understanding of the biological functions of GPCR by elucidating how observed differences in function between closely related adrenergic receptor subtypes are dependant upon the differences in structure of key domains.
The Role of α1-Andenergic Receptors (AR) in disease
Hypertension
Aging related diseases place a large social and economic burden on Australia. Diseases such as cardiovascular disease have increase incidence as we age. Improved pharmaceutical management of these conditions is required. The current research within the laboratory is concerned with understanding the mechanisms underlying adrenergic receptor function. Cell communication through these receptors regulates, among other processes, blood pressure. Our knowledge of how these receptors work at a molecular level, and why very similar subtypes differ in their functions, is limited. Our research will enhance this understanding and in the future lead to the development of more effective and safer medications targeting these receptors.
The Role of α1-AR in Prostate Cancer
Prostate cancer is a leading cause of cancer deaths in men. Epidemiological studies have suggested that the use of α1-AR antagonists, in the treatment of benign prostate hyperplasia, reduces the risk of prostate cancer. Moreover, recent studies have demonstrated α1-AR mediated proliferation of prostate cancer cell lines via signalling through TRP channels. We hypothesis that the α1D–AR is a prime target for drug development for a range of prostate cancers.
Current Research
The Molecular Pharmacology Laboratory is exploring the mechanisms of GPCR regulation and activation via:
(i) examination of conserved residues within rhodopsin-like GPCRs and the role these residues play in receptor expression and activation, and
(ii) a drug discovery program, in collaboration with A/Profs Renate Griffith and Larry Wakelin, studying novel chemical frameworks as the basis of new á1-adrenergic and 5HT-1 receptor subtype selective compounds for treatment of prostate cancer.
Projects available for Research Students
Project 1
The role of the second extracellular (E2) loop of GPCRs in activation of adrenergic receptors. This project will access the role key residues within the E2 loop play in á1-AR activation.
Project 2
Design and development for selective modulators of the á1D-AR. In this study newly designed and synthesised compounds will be tested to determine their affinities, potency, efficacy and selectivity for the á1D-AR.
Project 3
The role of the conserved proline of helix 6 in the expression and activation of adrenergic receptors. This study is examining mechanisms that control the activation and expression of adrenergic receptors.
Project 4
The role of á1-adrenergic and 5HT-1 receptor subtypes in the proliferation of prostate cancer. The project will examine the expression patterns of the receptor subtypes and their ability to promote the proliferation of prostate cancer cell lines.
Researchers
Ms Sevvandi Senadheera
Ms Viviane Richter
Publications
McNeil CJ, Nwagwu MO,
Finch AM, Page KP, Thain A, McArdle HJ, Ashworth CJ. Glucocorticoid exposure and tissue gene expression of 11β HSD-1, 11 β HSD-2, and glucocorticoid receptor in a porcine model of differential fetal growth. Reproduction 2007 133:653–661
Du XJ, Gao XM, Kiriazis H, Moore XL, Ming Z, Su Y,
Finch AM, Hannan RA, Dart AM, Graham RM. Transgenic α1A-adrenergic activation limits post-infarct ventricular remodeling and dysfunction and improves survival. Cardiovasc Res. 2006 71(4):735-43.
Finch AM, Graham RM. The a1D-adrenergic receptor: Cinderella or ugly stepsister. Mol Pharmacol. 2006 69(1):1-4.
Finch AM, Sarramegna V, Graham RM. Ligand binding, activation and agonist trafficking. In: The Adrenergic Receptors in the 21st Century, Perez DM (Ed.) Humana Press 2005 pp. 25-86
McNeil CJ,
Finch AM, Page KR, Clarke SD, Ashworth CJ, McArdle HJ. The effect of fetal pig size and stage of gestation on tissue fatty acid metabolism and profile. Reproduction. 2005 129(6):757-63.
Du XJ, Fang L, Gao XM, Kiriazis H, Feng X, Hotchkin E,
Finch AM, Chaulet H, Graham RM. Genetic enhancement of ventricular contractility protects against pressure-overload-induced cardiac dysfunction. J Mol Cell Cardiol. 2004 37(5):979-87.
Finch AM, Yang LG, Nwagwu MO, Page KR, McArdle HJ, Ashworth CJ. Placental transport of leucine in a porcine model of low birth weight. Reproduction. 2004 128(2):229-35.
McGinty SJ,
Finch A, Griffith R, Graham RM, Bremner JB. Synthesis and biological evaluation of bicyclic and tricyclic substituted nortropane derivatives: discovery of a novel selective α1D-adrenergic receptor ligand. Bioorg Med Chem. 2004 12(21):5639-50.
Page KR, Ashworth CJ, McArdle HJ,
Finch AM, Nwagwu MO. Sodium transport across the chorioallantoic membrane of porcine placenta involves the epithelial sodium channel (ENaC) J Physiol 2003 547(3): 849-857
Finch AM, Antipatis C, Pickard AR, Ashworth CJ. Patterns of fetal growth within Large White x Landrace and Chinese Meishan gilt litters at three stages of gestation Reproduction Fertility and Development 2002; 14 (7): 419-425 2002
Rooke JA, Sinclair AG, Edwards SA, Cordoba R, Pkiyach S, Penny PC, Penny P,
Finch AM, and Horgan GW. The effect of feeding salmon oil throughout on pre-weaning mortality of piglet. Animal Science, 2001, 73:489-500.
Ashworth CJ,
Finch AM, Page KR,.Nwagwu MO and.McArdle HJ Causes and consequences of fetal growth retardation in the pig. Reproduction Supplement, 2001, 58. 233-246.
Paczkowski NJ,
Finch AM, Whitmore JB, Short AJ, Wong AK, Monk PN, Cain SA, Fairlie DP, Taylor SM. Pharmacological characterization of antagonists of the C5a receptor. Br J Pharmacol. 1999;128(7):1461-6.
Finch AM, Wong AK, Paczkowski NJ, Wadi SK, Craik DJ, Fairlie DP, Taylor SM. Low-molecular-weight peptidic and cyclic antagonists of the receptor for the complement factor C5a. J Med Chem. 1999;42(11):1965-74.