Nicotinic Receptors

Using chemistry to understand nicotinic acetylcholine receptors. Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand gated ion channels found distributed throughout the body, controlling a wide range of functions ranging from muscular contraction, memory and cognition, and inflammatory processes. Our background in organic chemistry, enzymology and molecular modeling has enabled us to develop and test structure-based hypotheses regarding functional properties of antagonists, agonists, silent agonists (desensitizers that form conductive complexes with positive allosteric modulators (PAMs)), and ago-PAMs, compounds with the dual ability to uniquely function as both a PAM and an agonist. Working under the observation that silent agonists are mediating anti-inflammatory effects we seek to develop new compounds that have enhanced properties. We are modeling the receptor dynamics to gain insights as to structural features of ligands that promote desensitized states. Another current project is aimed at elucidating the basis for nAChR activity from Areca nut extracts and related compounds, with the important goal of developing superior smoking cessation therapeutics.

Selected references:

  1. Horenstein, N.A.; Papke, R.L.; Kulkarni, A.R.; Chaturbhuj, G.U.; Stokes, C.; Manther, K.; Thakur, G.A.(2016) “Critical molecular determinants of α7 nicotinic acetylcholine receptor allosteric activation: separation of direct allosteric activation and positive allosteric modulation” J. Biol. Chem. 291, 5049-5067.

  2. Quadri, M., Papke R.L., Horenstein, N.A. (2016) “Dissection of N,N-diethyl-N’-phenylpiperazines as α7 nicotinic receptor silent agonists.” Bioorg Med Chem. 24, 286-293.

  3. Papke RL, Horenstein NA, Stokes C (2015) Nicotinic Activity of Arecoline, the Psychoactive Element of “Betel Nuts”, Suggests a Basis for Habitual Use and Anti-Inflammatory Activity. PLoS ONE 10(10): e0140907. doi:10.1371/journal.pone.0140907

  4. Papke,R.L.; Chojnacka,K.; Horenstein,N.A. (2014) The Minimal Pharmacophore for Silent Agonism of the α7 Nicotinic Acetylcholine Receptor” JPET, 350, 665-680.

  5. Chojnacka, K.; Papke,R.L. and Horenstein, N.(2013). “Synthesis and evaluation of a conditionally-silent agonist for the α7 nicotinic receptor” Bioorg. Med. Chem. Lett. 23, 4145-4149.

  6. Wang, Jingyi; Papke, Roger L.; Stokes, Clare; Horenstein, Nicole A. “PotentialState-selective Hydrogen Bond Formation Can Modulate Activation and Desensitization of the α7 Nicotinic Acetylcholine Receptor”J. Biol. Chem. (2012), 287, 21957-21969.