Dopamine and serotonin receptors are central to brain function, yet are extremely challenging to study, especially in precise regions and narrow timescales. This is because traditional drugs for these receptors are subject to diffusion and other pharmacokinetic and pharmacodynamic factors that limit the spatiotemporal precision of experimental outcomes. Optical control has emerged as an excellent method to control neurons with the spatial and temporal resolution unavailable with drugs, however, methods to create light-controlled non-mutant receptors are lacking. Our ultimate goal is to create new tools to study dopamine and serotonin GPCRs in living mammals, without the need for genetic manipulation. To do this, we are synthesizing both broad (multiple subtypes) and specific modulators of dopamine and serotonin receptors, with an overall scheme of: 1) pharmacophore, 2) photoresponsive group, and 3) covalent handle. Broadly-acting pharmacophores are derivatives of apomorphine and ergoline alkoloids, and specific modulators are derivatives of FDA-approved drugs including ropinirole and pramipexole. Here, we report on the synthesis of new probe molecules, their evaluation in functional assays in human and rodent cell lines and primary cells, and proteomic analysis of probe targets via SILAC (Stable Isotope Labeling by/with Amino acids in Cell culture).

Photoresponsive ligands for dopamine and serotonin receptors: Synthesis and proteomics-based target identification

ACS Spring 2022

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