Nicotinic Receptors of the Neuronal and Non-neuronal Cholinergic Systems as Therapeutic Targets: Opportunities and Limitations

Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughtout the body. Classically, nAChRs were considered to mediate fast synaptic transmission, typified by muscle and ganglionic nAChRs. Now there is a vast diversity of subtypes of “neuronal” nAChRs, expressed in both neurons and non-neuronal cells, where they exhibit a remarkable range of cellular and subcellular locales, signaling mechanisms, and cellular functions, with a more modulatory or integrative role predominating in the central nervous system and non-neuronal cholinergic system. Thus, nAChRs contribute to many brain functions and physiological processes, and are implicated in a host of associated disease states. This prompted substantial interest from the pharmaceutical industry in the quest for novel therapeutic drugs. While this activity has generated many new compounds that are valuable tools for better understanding nAChR function and regulation, the translation of promising preclinical candidates to new therapeutics has been almost totally disappointing. After surveying the diversity of the nAChR family and the opportunities that they present for drug discovery, factors that have limited the successful therapeutic exploitation of nAChRs are discussed.