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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19MH085193-05
Application #
8547822
Study Section
Special Emphasis Panel (ZMH1-ERB-C (04))
Program Officer
Brady, Linda S
Project Start
2009-08-10
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$819,419
Indirect Cost
$145,364
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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
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
Zhang, Hankun; Tuckmantel, Werner; Eaton, J Brek et al. (2012) Chemistry and behavioral studies identify chiral cyclopropanes as selective ýý4ýý2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. J Med Chem 55:717-24
Liu, Jianhua; Yu, Li-Fang; Eaton, J Brek et al. (2011) Discovery of isoxazole analogues of sazetidine-A as selective ?4?2-nicotinic acetylcholine receptor partial agonists for the treatment of depression. J Med Chem 54:7280-8
Wu, Jie; Lukas, Ronald J (2011) Naturally-expressed nicotinic acetylcholine receptor subtypes. Biochem Pharmacol 82:800-7
Caldarone, Barbara J; Wang, Daguang; Paterson, Neil E et al. (2011) Dissociation between duration of action in the forced swim test in mice and nicotinic acetylcholine receptor occupancy with sazetidine, varenicline, and 5-I-A85380. Psychopharmacology (Berl) 217:199-210
Liu, Jianhua; Eaton, J Brek; Caldarone, Barbara et al. (2010) Chemistry and pharmacological characterization of novel nitrogen analogues of AMOP-H-OH (Sazetidine-A, 6-[5-(azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol) as ?4?2-nicotinic acetylcholine receptor-selective partial agonists. J Med Chem 53:6973-85