The goal of this NCDDDG research program is to identify new nicotinic agents that can be used in the treatment of depression. The lead compounds in this endeavor belong to the AMOP-H-OH (6-[5-(azetidin-2-ylmethoxy)-pyridin-3-yl]-hex-5-yn-1-ol) family of products. Preliminary studies show high affinities and selectivities of some of these agents for specific nicotinic acetylcholine receptor (nAChR) subtypes that correlate very well with drug antidepressant signatures as assessed by behavioral studies. Our working hypothesis is that drugs having high potency as partial agonists and that are truly selective for nAChRs composed of a4 and -32 subunits (a4p2-nAChRs) will have desired antidepressant activities. The research program is constructed around three, interlacing projects and supported by an administrative core. In the medicinal chemistry Project 1, we will design and synthesize new AMOP-H-OH analogs by varying their steric and stereoelectroman nAChR subtypes naturally or heterologously expressed in mammalian cells or Xenopus oocytes. This work will define whether new ligands act as full or partial agonists, as competitive or non-competitive antagonists, as open or closed channel blockers, or as positive or negative allosteric modulators at functional nAChRs based on established electrophysiological recording techniques and higher-throughput isotopic ion flux assays when possible. In Project 3, behavioral profiles for new ligands also will be determined using the innovative, powerful and high-throughput SmartCube?1/2 system, augmented by more classical methods, to assess drug activities as antidepressants. The studies will be conducted in a series of iterations, with in vitro nAChR subtype pharmacological profiling, modeling, and in vivo behavioral testing serving to inform synthetic strategies toward compounds that are optimized to have progressively superior nAChR subtype selectivity and behavioral activity The bestrs related to emotion and mood. However, the major focus of the work is to develop new antidepressant medications.
There still exists an important medical need for antidepressants exhibiting faster onsets of action, fewer side effects, and that act pharmacologically in new ways. Therefore, we have chosen to focus our efforts on the development of our nAChR ligands as antidepressants. However, we remain open to possible use of the same compounds in a number of other clinical applications, including treatment of nicotine dependence, schizophrenia, and pain.
|Zhang, Han-Kun; Eaton, J Brek; Fedolak, Allison et al. (2016) Synthesis and biological evaluation of novel hybrids of highly potent and selective ?4?2-Nicotinic acetylcholine receptor (nAChR) partial agonists. Eur J Med Chem 124:689-697|
|Onajole, Oluseye K; Vallerini, Gian Paolo; Eaton, J Brek et al. (2016) Synthesis and Behavioral Studies of Chiral Cyclopropanes as Selective ?4?2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile. Part III. ACS Chem Neurosci 7:811-22|
|Liu, Q; Kuo, Y-P; Shen, J et al. (2015) Roles of nicotinic acetylcholine receptor ? subunit cytoplasmic loops in acute desensitization and single-channel features. Neuroscience 289:315-23|
|Eaton, J Brek; Lucero, Linda M; Stratton, Harrison et al. (2014) The unique ?4+/-?4 agonist binding site in (?4)3(?2)2 subtype nicotinic acetylcholine receptors permits differential agonist desensitization pharmacology versus the (?4)2(?2)3 subtype. J Pharmacol Exp Ther 348:46-58|
|Yu, Li-Fang; Zhang, Han-Kun; Caldarone, Barbara J et al. (2014) Recent developments in novel antidepressants targeting ?4?2-nicotinic acetylcholine receptors. J Med Chem 57:8204-23|
|Liu, Qiang; Xie, Xitao; Lukas, Ronald J et al. (2013) A novel nicotinic mechanism underlies ?-amyloid-induced neuronal hyperexcitation. J Neurosci 33:7253-63|
|Zhang, Han-Kun; Yu, Li-Fang; Eaton, J Brek et al. (2013) Chemistry, pharmacology, and behavioral studies identify chiral cyclopropanes as selective ?4?2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. Part II. J Med Chem 56:5495-504|
|Yuan, Yang; Yu, Li-Fang; Qiu, Xi et al. (2013) Pharmacokinetics and brain penetration of LF-3-88, (2-[5-[5-(2(S)-azetidinylmethoxyl)-3-pyridyl]-3-isoxazolyl]ethanol), a selective ?4?2-nAChR partial agonist and promising antidepressant. J Chromatogr B Analyt Technol Biomed Life Sci 912:38-42|
|Zhang, Han-Kun; Eaton, J Brek; Yu, Li-Fang et al. (2012) Insights into the structural determinants required for high-affinity binding of chiral cyclopropane-containing ligands to ?4?2-nicotinic acetylcholine receptors: an integrated approach to behaviorally active nicotinic ligands. J Med Chem 55:8028-37|
|Yu, Li-Fang; Tuckmantel, Werner; Eaton, J Brek et al. (2012) Identification of novel ýý4ýý2-nicotinic acetylcholine receptor (nAChR) agonists based on an isoxazole ether scaffold that demonstrate antidepressant-like activity. J Med Chem 55:812-23|
Showing the most recent 10 out of 17 publications