Allosteric Targeting of Dopamine D2 Receptors: A New Treatment for Parkinson’s Disease

The central premise of this proposal is that a detailed mechanistic understanding of allostery at the D2R will enable the progression of our first-in-class allosteric modulators towards novel treatments for Parkinson's disease (PD). We will first explore the structural determinants of the allosteric behaviour of our initial first in class PAM. We will generate a comprehensive set of analogues of this initial ‘hit’ compound and measure their activity at all five dopamine receptor subtypes expressed in a model cell background. We will use radioligand binding and functional measures of receptor activation in combination with novel analytical approaches to quantify allosteric ligand action. This will allow us to understand the selectivity of these analogues for the different dopamine receptors and give insight into how they exert their effect. For example we can determine if they act to modulate dopamine efficacy and/or affinity, and quantify the magnitude of these effects. We can then relate these quantitative measures back to the ligand structure to build up an activity relationship that will allow us to develop improved PAMs of the D2R.

We will then extend these studies into a well validated animal model that is predictive for efficacy in reversing symptoms of PD. We will test selective novel PAMs in this experimental paradigm. We can then correlate the efficacy of our novel PAMs in this model with their in vitro parameters of efficacy. This will allow us to answer key translational questions, for example: Is modulation of dopamine efficacy or affinity most desirable for efficacy, what is the right amount of positive cooperativity with dopamine for efficacy. Together these studies will provide a solid platform for the development of novel allosteric drugs for the treatment of the symptoms of PD.