title: Central nicotinic receptors: structure, function, ligands, and therapeutic potential.
abstract: The growing interest in nicotinic receptors, because of their wide expression in neuronal and non-neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between alpha4beta2 and alpha7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high-throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials.
authors.affiliation: Laboratory of Design, Synthesis, and Study of Biologically Active Heterocycles (HeteroBioLab), Department of Pharmaceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy. novella.romanelli@unifi.it
authors.forename: M Novella
authors.initials: MN
authors.lastname: Romanelli
authors.forename: Paola
authors.initials: P
authors.lastname: Gratteri
authors.forename: Luca
authors.initials: L
authors.lastname: Guandalini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Martini
authors.forename: Claudia
authors.initials: C
authors.lastname: Bonaccini
authors.forename: Fulvio
authors.initials: F
authors.lastname: Gualtieri
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016503:Drug Delivery Systems; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D018722:Nicotinic Agonists / Q000627:therapeutic use; D018733:Nicotinic Antagonists / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000145:classification / Q000378:metabolism / Q000502:physiology*
chemical_list: D008024:Ligands; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic