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Supervisor 1: Jillian Baker

Supervisor 2: Shailesh Mistry

Funding Status: we will select the right option (competition funded studentships; Home and EU student eligibility)

Application deadline: 16th January 2015

Project Title: Determination of the ligand pharmacophore required for secondary conformation activation of the human β1-adrenoceptor

Project Description (500 words): (the text in bold to preface anything else)

The Universities of Nottingham and Monash have launched a joint PhD programme at the cutting edge of molecular pharmacology and drug discovery and are recruiting exceptional calibre applicants of any EU nationality for a 4-year research programme including a full year of study at Monash University, Australia. Upon admission to the programme students would undertake 3 rotations from a bank of available projects prior to selecting a final project.

Background: The human β1-adrenoceptor exists in two active forms: a high affinity conformation, activated by catecholamines e.g. adrenaline where β-blockers bind with high affinity, and a secondary low affinity conformation, activated by CGP 12177, where β-blockers bind with low affinity (Kaumann and Molenaar, 2008). Although this secondary conformation has been demonstrated in cells, tissues (including human) and whole animals, and the concentrations of β-blockers given to patients with heart disease are sufficient to occupy this secondary conformation, the clinical relevance remains unknown.

Several β-blockers activate this secondary conformation (Baker et al., 2003; Baker 2010). We know which parts of the receptors are important for this secondary conformation (Baker et al., 2014) but not which chemical moieties are needed for this activation.

Baker and Mistry have a chemistry-pharmacology collaboration examining β-adrenoceptor ligands (Mistry et al., 2013). This project uses the expertise of both disciplines to, for the first time, begin to understand the chemical moieties needed for this unusual pharmacological phenomenon.

Aims and project plan: This project aims to understand the structure-activity relationships of several established β-blockers with respect to their affinity for, and ability to activate, the secondary conformation of the human β1-adrenoceptor. Starting with drugs known to activate the secondary conformation, stepwise structural modifications will be made in these compounds to generate a library of analogues. This library will be examined in existing pharmacological assays to determine which the changes influence binding and function at both the primary catecholamine and secondary conformations of the receptor. This will be an iterative process whereby information gained from the first series of analogues will determine subsequent structural modifications, with an aim to engineer a set of novel molecules with varying ability to interact with the secondary conformation. Finally, following the suggestions that two CGP 12177 molecules may be required to activate the secondary conformation, bitopic ligands will then be made (ligands comprising of two molecules stuck together e.g. two CGP 12177 molecules or CGP 12177 and another β-blocker) to investigate whether secondary conformation interactions can be augmented if two molecules are tethered together.

Student training and skills: The student will develop skills in compound design and synthesis, including using a variety of equipment (e.g. standard flask-based, microwave and parallel synthesis), purification techniques (e.g. normal and reverse-phase chromatography, recrystallisation) and spectral techniques (e.g. 1D and 2D nuclear magnetic resonance spectroscopy, high-resolution mass-spectrometry, optical rotation of chiral compounds, infra-red spectroscopy). The student will understand the principles underpinning organic chemistry and presentation and report synthetic strategies and data. The student will also learn sterile tissue culture techniques, several pharmacological functional assays and to plot, analyse and present pharmacological data.

Timescale: The student will spend the first 2 years in Nottingham. The student will then spend a year in Monash University working with Prof. Scammells, who has developed expertise in the design and synthesis of bitopic ligands before returning to Nottingham to pharmacologically test these ligands and still have time to synthesize a few further ligands to optimise their novel molecules.

Interviews will take place in Nottingham in person or via Skype as appropriate.

Funding Notes: Students of UK and other EU nationalities are eligible to apply. Study fees and a tax-free stipend of at least £13,863 (subject to confirmation) for 4-years (3 years in Nottingham plus 1 year at Monash) is provided. Travel expenses associated with the year of study in Australia will be paid.

References (optional):

Baker JG (2005) J. Pharmacol Exp Ther. 313: 1163-1171.

Baker JG (2010) Br J Pharmacol 160: 148-161.

Baker JG, Hall IP, and Hill SJ (2003) Mol Pharmacol 63: 1312-1321.

Baker JG, Proudman RGW, Hill SJ (2014) Mol Pharmacol. 85: 811-829

Kaumann AJ, and Molenaar P (2008) Pharmacol Ther. 118: 303-336.

Mistry SN, Baker JG, Fischer PM, Hill SJ, Gardiner SM, Kellam B (2013) J Med Chem 56: 3852-3865.

Project classification: Medicinal chemistry, Molecular pharmacology

Application Enquiries:

Name: Jillian Baker (please delete as appropriate or to the School’s Postgraduate Director Ian Kerr ()

Email:

Applications: Applications consisting of a CV and covering letter should be sent to Professor Steve Hill () or Dr Ian Kerr ().