The dopamine D1 receptor plays an important role within the central nervous system in motor activity, reward, and cognitive functions including working memory, attention, and executive function. Selective D1 agonists are active in animal models relevant to several clinical applications including Parkinson’s disease, schizophrenia, mood disorders, sleep disorders, and Alzheimer’s disease. However, attempts to develop D1 agonists for clinical use have historically encountered challenges with dopamine receptor subtype selectivity, receptor desensitization, poor ADME/PK properties, or dose limiting side effects. Positive allosteric modulation of GPCR signaling offers potential advantages for therapeutic intervention over direct receptor activation by small molecule agonists.   Positive allosteric modulators (PAMs) amplify the response to the endogenous ligand 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. Due to greater structural diversity in GPCR allosteric binding sites there is also the potential for greater receptor subtype selectivity.  Thus, PAMs may have advantages over direct-acting agonists in terms of margin of safety and side-effect profile. At Lilly, a series of tetrahydroisoquinoline-based D1 PAMs has been developed that significantly increase the affinity of dopamine for the D1 receptor (high alpha-shift) and provide excellent D1 subtype selectivity. Multi-parameter optimization of molecules in this series resulted in the identification of mevidalen (LY3154207), a potent and selective D1 PAM currently in clinical development for the treatment of symptomatic Lewy body dementia.

Discovery of mevidalen, a novel dopamine D1 positive allosteric modulator for the treatment of neurodegenerative disorders

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ACS Fall 2022

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