Caged Neuromodulators: Design and Synthesis of Double-Caged Dopamine, a Novel Probe of Dopaminergic Function

Abstract

Rapid release of the neuromodulator dopamine has recently been linked to important cognitive processes such as reward-based learning and movement, making replication of fast dopaminergic transmission an attractive area of research. Caged neurotransmitters are a novel optical technology that enable the light-controlled, near-instantaneous release of free neurotransmitter from a chemical “cage” and subsequent activation of surrounding neurons with high spatiotemporal precision. Chemical two-photon uncaging, which attaches two inactivating groups to the neurotransmitter, improves the spatial resolution, stability, inertness, and cost of uncaging by requiring two simultaneous photocleavages to release the substrate. Uncaging therefore offers a powerful optical means of neurostimulation with several advantages over alternative techniques. Until recently, however, few effective forms of caged dopamine have been synthesized. Described herein is the design and synthesis of two novel iterations of caged dopamine: bis-CyHQ-DA and bis-CNB-DA. These compounds, the first double-caged forms of dopamine to be created, will contribute to the investigation of dopamine’s cellular and behavioral effects.