Photoswitchable ligands for the optical control of α7 nicotinic acetylcholine receptors: synthesis and photochromic characterization

The α7 nicotinic acetylcholine receptor (α7 nAChR) is widely distributed in the human organism, where it mediates many physiological and pathological processes. In the central nervous system, it is expressed both on neuronal and non-neuronal cells, where it controls cognitive and mnemonic processes, sensory gating and neuroinflammation, and it is thus involved in the etiopathology of several diseases, such as Alzheimer’s, depression, schizophrenia, attention-deficit/hyperactivity disorder (ADHD). In the periphery, it is essential for the survival of α7 dependent tumours, which are the most predominant type of lung cancer in the population. Therefore, alpha7 modulators have a huge therapeutic potential, but their clinical translation is hampered by the lack of adequate safety, generally because of low specificity. In addition, even though a vast pharmacological toolset to study α7 mediated functions has been developed, control of central α7 nAChRs with high spatiotemporal precision is missing. To address these issues, we have developed a small group of photoswitchable α7 nAChR ligands. Light is in fact an unparalleled tool as a noninvasive regulatory signal for pharmacological and biological applications, since it can be delivered with high spatiotemporal precision. An emerging light-based approach is photopharmacology, which relies on the use of reversibly photoswitching drugs. Our photoisomerizable compounds were designed by “azologization” of selective α7 nAChR agonists. In this work, I will present the design, the chemical synthesis, and the characterization of the photochromic properties of these novel potential photoswitchable α7 ligands.