Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are implicated in a wide range of physiological functions, pathological processes and pharmacological effects. These receptors are the initial targets of nicotine and play an essential role in the development of nicotine addiction. In addition, these receptors may also be involved in developments of other addictions and in certain CNS disorders, including schizophrenia. Efforts to develop drugs targeting nAChRs have focused mainly on the ability of ligands to activate nAChRs. We hypothesize that many of the in vivo effects of nicotine in the CNS are mediated mainly by the desensitization of neuronal nAChRs, predominantly the 04(32 nAChRs. Based on our studies of in vitro pharmacological properties of sazetidine-A, a novel ligand that selectively desensitizes a4p2 nAChRs, we further hypothesized that (1) a nicotinic ligand that selectively desensitizes a4(32 nAChRs in vitro will produce some of the important in vivo effects of nicotine;and (2) such selective desensitizers of a4p2 nAChRs are potential therapeutic agents to aid smoking cessation. Based on these hypotheses, we propose to develop novel nicotinic therapeutics based desensitization of nAChR, rather than on activation of them. In the Project 1, our objective is to use in vitro pharmacological methods to profile novel ligands. We propose four Specific Aims to accomplish the objective:
Aim 1, study equilibrium binding properties of all new ligands;
Aim 2, study functional properties of new ligands using 86Rb+ efflux assays;
Aim 3, study functional properties of new ligands using whole-cell patch clamp techniques;
and Aim 4, characterize the pharmacological mechanisms related to desensitization induced by the novel ligands.
The Aims of the Project 1 are closely related to proposed research in Project 2 (studies in animal behavioral models) and Project 3 (medicinal chemistry and animal tests for acute toxicity). We hope the collaborated efforts of the three projects will lead to drug candidates for Investigative New Drug applications, which may be used for treating nicotine addiction.
Tobacco use and nicotine addiction are an immense public health problem, and the health costs associated with smoking are estimated as $75 billion per year in the U.S. Current treatments for nicotine addiction are not adequate. The goal of this NCDDDG is to develop smoking cessation drugs to help the nearly 50 million people in N. America and 1 billion people worldwide end their addiction to nicotine and stop smoking.
|Dezfuli, Ghazaul; Kellar, Kenneth J; Dretchen, Kenneth L et al. (2016) Evidence for the role of Î²2* nAChR desensitization in regulating body weight in obese mice. Neuropharmacology 110:165-74|
|Forcelli, Patrick A; Turner, Jill R; Lee, Bridgin G et al. (2016) Anxiolytic- and antidepressant-like effects of the methadone metabolite 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP). Neuropharmacology 101:46-56|
|Kong, Hyesik; Song, Jun-ke; Yenugonda, Venkata Mahidhar et al. (2015) Preclinical studies of the potent and selective nicotinic Î±4Î²2 receptor ligand VMY-2-95. Mol Pharm 12:393-402|
|Tuan, Edward W; Horti, Andrew G; Olson, Thao T et al. (2015) AT-1001 Is a Partial Agonist with High Affinity and Selectivity at Human and Rat Î±3Î²4 Nicotinic Cholinergic Receptors. Mol Pharmacol 88:640-9|
|Hussmann, G Patrick; DeDominicis, Kristen E; Turner, Jill R et al. (2014) Chronic sazetidine-A maintains anxiolytic effects and slower weight gain following chronic nicotine without maintaining increased density of nicotinic receptors in rodent brain. J Neurochem 129:721-31|
|Afshordel, Sarah; Wood, Wellington Gibson; Igbavboa, Urule et al. (2014) Impaired geranylgeranyltransferase-I regulation reduces membrane-associated Rho protein levels in aged mouse brain. J Neurochem 129:732-42|
|Liu, Yong; Paige, Mikell; Olson, Thao T et al. (2014) Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A. Bioorg Med Chem Lett 24:2954-6|
|Burke, Dennis A; Heshmati, Pooneh; Kholdebarin, Ehsan et al. (2014) Decreasing nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats. Eur J Pharmacol 741:132-9|
|Levin, Edward D; Cauley, Marty; Rezvani, Amir H (2013) Improvement of attentional function with antagonism of nicotinic receptors in female rats. Eur J Pharmacol 702:269-74|
|Levin, Edward D; Sexton, Hannah G; Gordon, Karen et al. (2013) Effects of the sazetidine-a family of compounds on the body temperature in wildtype, nicotinic receptor Î²2-/- and Î±7-/- mice. Eur J Pharmacol 718:167-72|
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