Osteoporosis and asthma are highly prevalent diseases in Australia that can profoundly impact the quality of life of sufferers. Surprisingly, there is mounting evidence to suggest that the underlying symptoms of osteoporosis and asthma can be controlled by a common drug target: the calcium sensing receptor (CaSR). The CaSR is a Class C G protein-coupled receptor (GPCR) essential for life and widely expressed in human tissue to monitor extracellular calcium concentrations.
Allosteric modulators bind topographically distinct sites from the endogenous (orthosteric) receptor agonist, where they can reduce agonist affinity and/or efficacy, or themselves activate/inactivate a receptor. Allosteric modulators can make extremely attractive drug candidates - an allosteric site is typically less conserved between receptors than an orthosteric site, affording a high level of drug selectivity. Cinacalcet is an TGA approved allosteric modulator, which enhances the activity (positive allosteric modulator; PAM) of CaSR and is used for the treatment of hyperparathyroidism. However, the development of drugs that reduce CaSR activity (negative allosteric modulator; NAM), for the treatment of osteoporosis and asthma, has remained elusive. Indeed, allosteric modulator drug candidates, targeting the CaSR, have entered clinical trials for the treatment of osteoporosis, but have failed due to poor clinical efficacy.
Our work shows how a poor translation of pre-drug candidates for the CaSR is, in part, due to poor evaluation of their pharmacology and an over dependence on potency measurements against a single agonist concentration. Therefore, for our drug discovery program, we are using an operational model of allosterism fitted to functional signalling data, to calculate the affinity, efficacy and magnitude/direction of an allosteric effect (cooperativity) for evaluating our allosteric modulator drug candidates. Using in silico ligand screening with biological testing, we have identified new chemical scaffolds that modulate CaSR activity. Hence, we are synthesising these compounds and related analogues, to assess their activity using our improved analytical pharmacology methodology. It is hoped that this program will yield the high affinity compounds required to effectively target the CaSR for the treatment of osteoporosis and asthma.