The dopamine receptor D1 subtype (DRD1) is the most abundant dopamine receptor in the central nervous system, and plays an important role in motor activity, reward, and cognitive functions.  Catechol-based DRD1 orthosteric agonists have been extensively studied and are active in many clinically relevant disease models in preclinical species. In particular, these agonists were found to have excellent antiparkinsonian effects in humans and primate models of Parkinson’s disease (PD).  However, attempts to develop these agonists for clinical use have thus far been largely unsuccessful due to receptor desensitization, poor ADME/PK properties, and dose limiting side effects (e.g. hypotension). In addition, D1 agonists show a bell-shaped dose response curve on cognitive endpoints. Due to the high degree of structural homology between DRD5 and DRD1 receptors, selective DRD1 agonists have been difficult to design.  At Lilly, a positive allosteric modulator (PAM) approach to DRD1 activation has been developed to potentially address the issues associated with the orthosteric agonists. Pure PAMs do not have any direct effects themselves, but indirectly amplify the response to the endogenous agonist when and where the endogenous ligand is released, and thus have the ability to act in a more physiologically relevant way than direct-acting agonists, which activate all accessible receptors for as long as they are present. PAMs also bind to a site distinct from the orthosteric binding site that may have greater structural diversity and thus offer potential to achieve greater subtype selectivity. In this presentation, we will describe the discovery of LY3154207, an orally available, potent and selective DRD1 PAM currently in phase 2 clinical trials for the treatment of Parkinson’s disease dementia. Preclinical data supporting its clinical evaluation will be presented.<br/>

Discovery of LY3154207, a potent and selective dopamine receptor D1 positive allosteric modulator for the treatment of Parkinson’s disease dementia

256th National Meeting (2018)

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