Design and synthesis of the first selective ligands for the GPRC6A receptor – a novel human G-protein coupled receptor with unknown physiological function
Aim
The aim of the PhD project is to synthesise antagonists and positive allosteric modulators for the GPRC6A receptor using contemporary methods in synthetic organic chemistry. The main focus for the PhD student will be on the design and synthesis of GPRC6A ligands working with a wide range of chemistries, including multi-component reactions, heterocyclic chemistry, and amino acid chemistry. The Department of Medicinal Chemistry has an excellent infra-structure and the PhD student will utilise a range of advanced instruments and techniques on a daily basis. However, the PhD student will also be involved in all other medicinal chemistry / drug discovery aspects of the projects through regular meetings with members of the research group and our external collaborators.
The ultimate aim for the project is to identify ligands with nano-molar potency, high selectivity, good water solubility and high metabolic stability. Such compounds would be highly valuable as tools to delineate the physiological function and therapeutic potential of the GPRC6A receptor and could be commercialised as pharmacological probes. In a longer perspective we aim to develop compounds with oral bioavailability that could be licensed to the pharmaceutical industry.
Background
G-protein coupled receptors are known to be implicated in many important physiological processes making them targets for approximately 40% of marketed drugs.1 In 2005 Professor Hans Bräuner-Osborne’s group cloned a novel G protein-coupled receptor from human, mouse and rat termed GPRC6A.2-4 It is likely that GPRC6A is involved in pathophysiology making it a relevant drug target. However, a major obstacle to conduct detailed pharmacological studies is the lack of potent and selective ligands which could be used as pharmacological tools in vitro and in vivo.
Lead structures for synthetic optimisation
Using a computational chemistry approach termed "ligand inference of privileged structures",5 we have recently identified a class of allosteric modulators that bind to the 7TM domain of GPRC6A, via screening of a small focussed compound library. This result is a breakthrough as these compounds are the first GPRC6A selective antagonists ever identified.
Moreover, we have recently identified both positive and negative allosteric modulators by pharmacological screening of a large compound library. Three of the identified modulators belong to the same class of compounds, suggesting that it will be possible to design a potent ligand based on this scaffold.
The stage is now set to develop these hit structures into pharmacological probes / drug candidates through an iterative design, chemical synthesis, and pharmacological testing process.
The PhD student will be in charge of the synthetic aspects of the project and will benefit from the fact that a wide variety of the required building blocks are commercially available, allowing for a rapid and detailed structure-activity-relationship study.
Focus of the present PhD project
The focus of the present PhD project is to design and synthesise analogues of the pharmacological lead structures described above. All compounds will subsequently be tested by pharmacologists in the group on recombinant GPRC6A receptor expressed in mammalian cells using our previously published pharmacological assay.4,6 The most promising compounds will be tested in vitro on cell lines and tissues which endogenously express the GPRC6A receptor. Finally, the most potent and metabolically stable compounds will be tested in vivo in mice and rats.
Overall, the candidate will obtain a strong knowledge of medicinal chemistry and drug design in a highly interdisciplinary environment.
Reference list
1. Lundstrom, K. The future of G protein-coupled receptors as targets in drug discovery. IDrugs 2005, 8 (909), 913.
2. Wellendorph, P.; Hansen, K. B.; Balsgaard, A.; Greenwood, J. R.; Egebjerg, J.; Brauner-Osborne, H. Deorphanization of GPRC6A: A promiscuous L-alpha-amino acid receptor with preference for basic amino acids. Mol. Pharmacol. 2005, 67 (3), 589-597.
3. Wellendorph, P.; Bräuner-Osborne, H. Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C G-protein-coupled receptor. Gene 2004, 335, 37-46.
4. Wellendorph, P.; Burhenne, N.; Christiansen, B.; Walter, B.; Schmale, H.; Bräuner-Osborne, H. The rat GPRC6A: Cloning and characterization. Gene 2007, 396, 257-267.
5. Gloriam, D. E.; Blaney, F. B.; Garland, S. L. Three Privileged Structures Paired with GPCR Targets -A tool for Target-specific Library Design and Lead-finding. Manuscript In preparation 2010.
6. Christiansen, B.; Hansen, K. B.; Wellendorph, P.; Bräuner-Osborne, H. Pharmacological characterization of mouse GPRC6A, an L-á-amino acid receptor with ability to sense divalent cations. Br. J. Pharmacol. 2007, 150, 798-807.
