TC-1734: An orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects
Open accessAbstract
The development of selective ligands targeting neuronal nicotinic acetylcholine receptors to alleviate symptoms associated with neurodegenerative diseases presents the advantage of affecting multiple deficits that are the hallmarks of these pathologies. TC-1734 is an orally active novel neuronal nicotinic agonist with high selectivity for neuronal nicotinic receptors. Microdialysis studies indicate that TC-1734 enhances the release of acetylcholine from the cortex. TC-1734, by either acute or repeated administration, exhibits memory enhancing properties in rats and mice and is neuroprotective following excitotoxic insult in fetal rat brain in cultures and against alterations of synaptic transmission induced by deprivation of glucose and oxygen in hippocampal slices. At submaximal doses, TC-1734 produced additive cognitive effects when used in combination with tacrine or donepezil. Unlike (-)-nicotine, behavioral sensitization does not develop following repeated administration of TC-1734. Its pharmacokinetic (PK) profile (half-life of 2 h) contrasts with the long lasting improvement in working memory (18 h) demonstrating that cognitive improvement extends beyond the lifetime of the compound. The very low acute toxicity of TC-1734 and its receptor activity profile provides additional mechanistic basis for its suggested potential as a clinical candidate. TC-1734 was very well tolerated in acute and chronic oral toxicity studies in mice, rats and dogs. Phase I clinical trials demonstrated TC-1734's favorable pharmacokinetic and safety profile by acute oral administration at doses ranging from 2 to 320 mg. The bioavailability, pharmacological, pharmacokinetic, and safety profile of TC-1734 provides an example of a safe, potent and efficacious neuronal nicotinic modulator that holds promise for the management of the hallmark symptomatologies observed in dementia.
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Several classes of nicotinic agonists have antidepressant actions in human studies and animal models, but several nicotinic antagonists have potent antidepressant effects.
“several classes of nicotinic agonists have antidepressant actions in both human studies and animal models (Ferguson et al., 2000; Gatto et al., 2004) but several nicotinic antagonists have shown to have potent antidepressant effects (Ferguson et al., 2000; Shytle et al., 2002).”
From It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood (2008) · cites this paper as Gatto et al., 2004
The α4/β2* subclass of nAChRs is necessary for the antidepressant-like effects of nicotinic antagonists.
“the α4/β2* subclass of nAChRs is necessary for the antidepressant-like effects of nicotinic antagonists as demonstrated in KO mice and using selective pharmacological agents (Gatto et al., 2004; Mineur et al., 2007; Rabenstein et al., 2006).”
From It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood (2008) · cites this paper as Gatto et al., 2004
Other nicotinic partial agonists such as sazetidine-A and ispronicline also have antidepressant effects.
“other nicotinic partial agonists such as sazetidine-A and ispronicline (TC-1734 or AZD3480) also have antidepressant effects (Gatto et al., 2004; Xiao et al., 2006).”
From Nicotine addiction and psychiatric disorders (2015) · cites this paper as Gatto et al., 2004
Cites
Nicotinic systems and cognitive function
Levin, E. D. (1992) · Psychopharmacology · doi:10.1007/bf02247415 · Cited by 511 · see citing works
Sahakian, B. J., Jones, G., Levy, R., Gray, J. A., & Warburton, D. M. (1989) · The British Journal of Psychiatry · doi:10.1192/bjp.154.6.797 · Cited by 494 · see citing works
Jones, G., Sahakian, B. J., Levy, R., Warburton, D. M., & Gray, J. A. (1992) · Psychopharmacology · doi:10.1007/bf02247426 · Cited by 476 · see citing works
Nicotinic receptor stimulation protects neurons against β‐amyloid toxicity
Kihara, T., Shimohama, S., Sawada, H., Kimura, J., Kume, T., Kochiyama, H., Maeda, T., & Akaike, A. (1997) · Annals of Neurology · doi:10.1002/ana.410420205 · Cited by 315 · see citing works
Akaike, A., Tamura, Y., Yokota, T., Shimohama, S., & Kimura, J. (1994) · Brain Research · doi:10.1016/0006-8993(94)91678-0 · Cited by 240 · see citing works
Nicotine Inhibits Amyloid Formation by the β-Peptide
Salomon, A. R., Marcinowski, K. J., Friedland, R. P., & Zagorski, M. G. (1996) · Biochemistry · doi:10.1021/bi9617264 · Cited by 220 · see citing works
Stimulation of α4β2 nicotinic acetylcholine receptors inhibits β-amyloid toxicity
Kihara, T., Shimohama, S., Urushitani, M., Sawada, H., Kimura, J., Kume, T., Maeda, T., & AKAIKE, A. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00138-3 · Cited by 193 · see citing works
Kaneko, S., Maeda, T., Kume, T., Kochiyama, H., Akaike, A., Shimohama, S., & Kimura, J. (1997) · Brain Research · doi:10.1016/s0006-8993(97)00556-8 · Cited by 193 · see citing works
Decker, M. W., Brioni, J. D., Sullivan, J. P., Buckley, M. J., Radek, R. J., Raszkiewicz, J. L., Kang, C. H., Kim, D. J., Giardina, W. J., & Wasicak, J. T. (1994) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)22339-4 · Cited by 180 · see citing works
Shaw, S., Bencherif, M., & Marrero, M. B. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204610200 · Cited by 172 · see citing works
Self-citationSummers, K. L., & Giacobini, E. (1995) · Neurochemical Research · doi:10.1007/bf01705545 · Cited by 150 · see citing works
RJR-2403: a nicotinic agonist with CNS selectivity I. In vitro characterization.
Bencherif, M., Lovette, M. E., Fowler, K., Arrington, S. R., Reeves, L., Caldwell, W. S., & Lippiello, P. M. (1996) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)21302-7 · Cited by 141 · see citing works
Self-citation(1966) · Food and Cosmetics Toxicology · doi:10.1016/s0015-6264(66)80532-1 · Cited by 140 · see citing works
The Pharmacology of (-)-Nicotine and Novel Cholinergic Channel Modulators
Brioni, J. D., Decker, M. W., Sullivan, J. P., & Arnerić, S. P. (1996) · Advances in pharmacology · doi:10.1016/s1054-3589(08)60950-3 · Cited by 134 · see citing works
Nicotine‐induced Protection Against Glutamate Cytotoxicity
Shimohama, S., AKAIKE, A., & Kimura, J. (1996) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1996.tb34445.x · Cited by 118 · see citing works
Marin, P., Maus, M., Desagher, S., Glowinski, J., & Prémont, J. (1994) · Neuroreport · doi:10.1097/00001756-199410000-00035 · Cited by 110 · see citing works
Multiple Central Nervous System Targets for Eliciting Beneficial Effects on Memory and Cognition
Buccafusco, J. J., & Terry, A. V. (2000) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)38924-4 · Cited by 107 · see citing works
In vitro neuroprotective properties of the novel cholinergic channel activator (ChCA), ABT-418
Donnelly‐Roberts, D. L., Xue, I. C., Arnerić, S. P., & Sullivan, J. P. (1996) · Brain Research · doi:10.1016/0006-8993(96)00063-7 · Cited by 103 · see citing works
Cosford, N. D. P., Bleicher, L. S., Herbaut, A., et al. (1996) · Journal of Medicinal Chemistry · doi:10.1021/jm960328w · Cited by 93 · see citing works
Chronic nicotinic stimulation and blockade effects on working memory
Levin, E. D., Briggs, S. J., Christopher, N. C., & Rose, J. E. (1993) · Behavioural Pharmacology · doi:10.1097/00008877-199304000-00010 · Cited by 92 · see citing works
(S)‐3‐メチル‐5‐(1‐メチル‐2‐ピロリジニル)イソキサゾール(ART418) 認知促進および抗不安活性を持つ新しいコリン作動性リガンド II in vivoの性質
Decker, M. W., Brioni, J. D., Sullivan, J. P., et al. (1994) · Journal of Pharmacology and Experimental Therapeutics · Cited by 92 · see citing works
Nicotine enhances the learning and memory of aged rats
Aren-, G. W., Sanberg, P. R., & Sengstock, G. J. (1995) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(95)00119-h · Cited by 90 · see citing works
Persistence of chronic nicotine-induced cognitive facilitation
Levin, E. D., Briggs, S. J., Christopher, N. C., & Rose, J. E. (1992) · Behavioral and Neural Biology · doi:10.1016/0163-1047(92)90399-o · Cited by 82 · see citing works
Bannon, A. W., Decker, M. W., Curzon, P., Buckley, M. J., Kim, D. J. B., Radek, R. J., Lynch, J. K., Wasicak, J. T., Lin, N., Arnold, W. H., et al. (1998) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37423-3 · Cited by 78 · see citing works
Nicotine rescues PC12 cells from death induced by nerve growth factor deprivation
Yamashita, H., & Nakamura, S. (1996) · Neuroscience Letters · doi:10.1016/0304-3940(96)12829-9 · Cited by 70 · see citing works
Jeyarasasingam, G., Tompkins, L., & Quik, M. (2002) · Neuroscience · doi:10.1016/s0306-4522(01)00488-2 · Cited by 68 · see citing works
Bontempi, B., Whelan, K. T., Risbrough, V. B., Rao, T. S., Buccafusco, J. J., Lloyd, G. K., & Menzaghi, F. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)29330-7 · Cited by 56 · see citing works
RJR-2403: a nicotinic agonist with CNS selectivity II. In vivo characterization.
Lippiello, P. M., Bencherif, M., Gray, J. A., et al. (1996) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)21303-9 · Cited by 48 · see citing works
Self-citation(-)-Nicotine Protects against Systemic Kainic Acid-Induced Excitotoxic Effects
Borlongan, C. V., Shytle, R. D., Ross, S. D., Shimizu, T., Freeman, T. B., Cahill, D. W., & Sanberg, P. R. (1995) · Experimental Neurology · doi:10.1006/exnr.1995.1103 · Cited by 46 · see citing works
TC-2559: A novel orally active ligand selective at neuronal acetylcholine receptors
Bencherif, M., Bane, A. J., Miller, C. H., et al. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00807-4 · Cited by 43 · see citing works
Self-citationIntravenous nicotine in a patient with Alzheimer's disease
NEWHOUSE, P. A., Sunderland, T., Thompson, K., et al. (1986) · American Journal of Psychiatry · doi:10.1176/ajp.143.11.1494 · Cited by 42 · see citing works
Obinu, M. C., Reibaud, M., Miquet, J.-M., Pasquet, M., & Rooney, T. (2002) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(02)00205-1 · Cited by 40 · see citing works
Self-citationSummers, K. L., Lippiello, P. M., & Giacobini, E. (1996) · Neurochemical Research · doi:10.1007/bf02532393 · Cited by 40 · see citing works
Arnerić, S. P., Anderson, D. J., Bannon, A. W., Briggs, C. A., Buccafusco, J. J., Brioni, J. D., Cannon, J. B., Decker, M. W., Donnelly‐Roberts, D. L., Gopalakrishnan, M., et al. (1995) · CNS Drug Reviews · doi:10.1111/j.1527-3458.1995.tb00274.x · Cited by 40 · see citing works
Targeting Neuronal Nicotinic Receptors: a Path to New Therapies
Bencherif, M., & Schmitt, J. D. (2002) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1568007023339094 · Cited by 34 · see citing works
Self-citationNanri, M., Kasahara, N., Yamamoto, J., Miyake, H., & Watanabe, H. (1997) · The Japanese Journal of Pharmacology · doi:10.1254/jjp.74.285 · Cited by 29 · see citing works
Janson, A. M., Hedlund, P. B., Fuxé, K., & von Euler, G. (1994) · Brain Research · doi:10.1016/0006-8993(94)91593-8 · Cited by 29 · see citing works
Chapter 5. Targeting nicotinic acetylcholine receptors: Advances in molecular design and therapies
Schmitt, J. D., & Bencherif, M. (2000) · Annual reports in medicinal chemistry · doi:10.1016/s0065-7743(00)35006-0 · Cited by 27 · see citing works
Self-citationSemba, J., Miyoshi, R., & Kito, S. (1996) · Brain Research · doi:10.1016/0006-8993(96)00926-2 · Cited by 26 · see citing works
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Levin, E. D., McClernon, F. J., & Rezvani, A. H. (2006) · Psychopharmacology · doi:10.1007/s00213-005-0164-7 · Cited by 820 · see citing works
PICCIOTTO, M., ADDY, N., MINEUR, Y., & BRUNZELL, D. (2008) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2007.12.005 · Cited by 451 · see citing works
Wilens, T. E., & Decker, M. W. (2007) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.07.002 · Cited by 164 · see citing works
Animal models of Alzheimer disease: historical pitfalls and a path forward
Cavanaugh, S. E. (2014) · ALTEX · doi:10.14573/altex.1310071 · Cited by 132 · see citing works
Andreasen, J., Olsen, G., Wiborg, O., & Redrobe, J. (2009) · Journal of Psychopharmacology · doi:10.1177/0269881108091587 · Cited by 101 · see citing works
Rollema, H., Guanowsky, V., Mineur, Y. S., Shrikhande, A., Coe, J. W., Seymour, P. A., & Picciotto, M. R. (2009) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2009.01.002 · Cited by 87 · see citing works
Nicotinic receptor-mediated reduction in l-DOPA-induced dyskinesias may occur via desensitization
Bordia, T., Campos, C., McIntosh, J. M., & Quik, M. (2010) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.162396 · Cited by 82 · see citing works
Dunbar, G. C., Inglis, F., Kuchibhatla, R., Sharma, T., Tomlinson, M., & Wamsley, J. (2007) · Journal of Psychopharmacology · doi:10.1177/0269881107066855 · Cited by 75 · see citing works
Self-citationNicotine addiction and psychiatric disorders
Kutlu, M. G., Parikh, V., & Gould, T. J. (2015) · International Review of Neurobiology · doi:10.1016/bs.irn.2015.08.004 · Cited by 65 · see citing works
Caldarone, B. J., Wang, D., Paterson, N. E., Manzano, M., Fedolak, A., Cavino, K., Kwan, M., Hanania, T., Chellappan, S. K., Kozikowski, A. P., et al. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2271-y · Cited by 47 · see citing works
Anderson, D. J., Malysz, J., Grønlien, J. H., El Kouhen, R., Håkerud, M., Wetterstrand, C., Briggs, C. A., & Gopalakrishnan, M. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.06.024 · Cited by 44 · see citing works
Andreasen, J. T., Redrobe, J. P., & Nielsen, E. Ø. (2012) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.11.004 · Cited by 43 · see citing works
- Authors
- Gatto, G. J., Bohme, G. A., Caldwell, W. S., Letchworth, S. R., Traina, V. M., Obinu, M. C., Laville, M., Reibaud, M., Pradier, L., Dunbar, G., & Bencherif, M.
- Corresponding author
- Bencherif, Merouane
- ORCID
- Pradier, Laurent
- Venue
- CNS Drug Reviews
- Publisher
- Wiley
- Published
- 2004-06
- Volume
- 10
- Issue
- 2
- Pages
- 147-166
- ISSN
- 1080-563X (ISSN-L)
- 1527-3458
- PMC
- PMC6741718
- OpenAlex
- W1980593483
- Cited by
- 111
- References
- 39
- Citations by year
- 2026: 2 · 2024: 1 · 2021: 3 · 2020: 3 · 2019: 1 · 2018: 5 · 2016: 3 · 2015: 8 · 2014: 12 · 2013: 6 · 2012: 12
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- CNS Drug Reviews (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- antidepressant effects, neuroprotection, memory enhancement, acetylcholine release, excitotoxicity, glucose deprivation, tacrine, donepezil, behavioral sensitization, pharmacokinetics, oral toxicity, dementia, neurodegenerative diseases, working memory
- MeSH terms
- Administration, Oral, Adolescent, Adrenocorticotropic Hormone, Adult, Animals, Antidepressive Agents, Cerebral Cortex, Cholinesterase Inhibitors, Cognition, Discrimination Learning, Dogs, Humans, Male, Memory, Middle Aged, Motor Activity, Pyridines, Receptors, Nicotinic, Reference Values, Sympathomimetics, Neuroprotective Agents, Nicotinic Agonists, Maze Learning, Toxicity Tests, Chronic, Mice, Rats
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