Photoactivatable drugs for nicotinic optopharmacology

Photostimulation techniques utilizing caged compounds have revolutionized neuroscience and provided a tool that has allowed precise probing of neural circuits and characterization of receptor behavior at the synaptic level. To date the range of receptors accessible through uncaging protocols has been limited due to the small number of ligands available in a caged format.

The authors describe a novel method for caging tertiary amines using an unconventional quaternary amine linkage. They successfully synthesized photoactivatable nicotine (PA-Nic), and demonstrate its use in 1- and 2-photon illumination protocols for photostimulation. Using brain slices they focused primarily on neurons in the Medial Habenula and showed that synthesized PA-Nic was specific to nicotinic acetylcholine receptors (nAChRs), and demonstrated a dose response relationship between light dose and biological response as measured by voltage clamp recording. Utilizing 1-P and 2-P laser point stimulation, they demonstrate spatial specificity, and provide preliminary findings showing the potential for PA-Nic for uncovering spatial mapping questions related to neurons with nAChRs.

The authors also propose the utility of their synthesis methods for developing photoactivatable versions of other compounds containing tertiary amines such as fentanyl and escitalopram.

In summary, this is a groundbreaking piece of work that greatly expands the potential pharmacological tool kit for optopharmacology studies.