title: Therapeutic potential of novel selective drugs targeting nicotinic acetylcholine receptors.
abstract: The potential therapeutic benefit of nicotinic ligands in a variety of neurodegenerative pathologies involving the CNS has energized research efforts to develop nicotinic acetylcholine receptor (nAChR) subtype-selective ligands (Bencherif and Schmitt, 2005). In particular, there has been a concerted effort to develop nicotinic compounds with selectivity for CNS nAChRs as potential pharmaceutical tools in the management of these disorders. Clinical and experimental data demonstrate a central role for alpha7 and alpha4beta2 nAChRs in cognitive function, sensory processing, mood, and neuroprotection (Bencherif and Schmitt, 2005; Buccafusco et al., 2005). The development of safe alpha7-selective ligands has been hampered by their lack of discrimination with hERG channels and 5-HT3 receptors. We have developed a number of compounds that display nanomolar affinity to the alpha7 and/or the alpha4beta2 receptor. Investigation of alpha7 functional activity showed a full range of activities from antagonists to full agonists without any significant activity at the human 5-HT3 receptor, P450 isozymes, hERG channels, or in the AMES test. Our findings demonstrate that potent and highly selective nAChR ligands can be designed.
authors.affiliation: Preclinical Research, Targacept Inc., Winston-Salem, NC 27101, USA. merouane.bencherif@targacept.com
authors.forename: Merouane
authors.initials: M
authors.lastname: Bencherif
authors.forename: Terry A
authors.initials: TA
authors.lastname: Hauser
authors.forename: Kristen G
authors.initials: KG
authors.lastname: Jordan
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gatto
mesh_terms: D000818:Animals; D018678:Cholinergic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D006801:Humans; D008024:Ligands; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*
chemical_list: D018678:Cholinergic Agents; D008024:Ligands; D018696:Neuroprotective Agents; D011978:Receptors, Nicotinic; D016291:Dizocilpine Maleate