Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders
Open accessAbstract
Muscarinic acetylcholine receptors (mAChRs) have long been viewed as viable targets for novel therapeutic agents for the treatment of Alzheimer's disease (AD) and other disorders involving impaired cognitive function. More recent evidence indicates that mAChR activators might also have utility in treating psychosis and other symptoms associated with schizophrenia and other central nervous system (CNS) disorders. Efforts to develop mAChR subtype-selective agonists have been hampered by difficulty in achieving high selectivity for individual mAChR subtypes important for CNS function (M(1) and M(4)) and adverse effects due to activation of peripheral mAChRs (especially M(2) and M(3)). Major advances have now been achieved in the discovery of allosteric agonists and positive allosteric modulators of M(1) and M(4) that show greater selectivity for individual mAChR subtypes than do previous mAChR agonists. Early studies indicate that these allosteric mAChR activators have properties needed for optimization as potential clinical candidates and have robust effects in animal models that predict efficacy in the treatment of AD, schizophrenia and related disorders.
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Initial efforts focused on developing orthosteric inhibitors that target active site endogenous ligands, but the selectivity of these inhibitors has been hindered by the high conservation of orthosteric binding sites in GPCRs.
“While initial efforts have focused on developing orthosteric inhibitors that target active site endogenous ligands (orthosteric site), the selectivity of these inhibitors has been hindered by the high conservation of orthosteric binding sites in GPCRs.296,297”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [297]
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Cites
The Synaptic Organization of the Brain
(2004) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780195159561.001.1 · Cited by 3,550 · see citing works
The Biochemical Basis of Neuropharmacology.
(1974) · Annals of Internal Medicine · doi:10.7326/0003-4819-81-4-575_2 · Cited by 1,882 · see citing works
The role of acetylcholine in learning and memory
Hasselmo, M. E. (2006) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2006.09.002 · Cited by 1,693 · see citing works
Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders
Jeffrey Conn, P., Christopoulos, A., & Lindsley, C. W. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2760 · Cited by 1,063 · see citing works
Self-citationAllosteric Modulation of G Protein–Coupled Receptors
May, L. T., Leach, K., Sexton, P. M., & Christopoulos, A. (2006) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105159 · Cited by 698 · see citing works
Bodick, N. C., Offen, W., Levey, A. I., Cutler, N. R., Gauthier, S. G., Satlin, A., Shannon, H. E., Tollefson, G. D., Rasmussen, K., Bymaster, F. P., et al. (1997) · Archives of Neurology · doi:10.1001/archneur.1997.00550160091022 · Cited by 687 · see citing works
Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development
Wess, J., Eglen, R. M., & Gautam, D. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2379 · Cited by 637 · see citing works
Selective Muscarinic Receptor Agonist Xanomeline as a Novel Treatment Approach for Schizophrenia
Shekhar, A., Potter, W. Z., Lightfoot, J., Lienemann, J., Dubé, S., Mallinckrodt, C. H., Bymaster, F. P., McKinzie, D. L., & Felder, C. C. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2008.06091591 · Cited by 563 · see citing works
Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice
Anagnostaras, S., Murphy, G. G., Hamilton, S. E., Mitchell, S. L., Rahnama, N. P., Nathanson, N. M., & Silva, A. J. (2002) · Nature Neuroscience · doi:10.1038/nn992 · Cited by 543 · see citing works
Re-emergence of striatal cholinergic interneurons in movement disorders
Pisani, A., Bernardi, G., Ding, J., & Surmeier, D. J. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.07.008 · Cited by 466 · see citing works
M1 Receptors Play a Central Role in Modulating AD-like Pathology in Transgenic Mice
Caccamo, A., Oddo, S., Billings, L. M., Green, K. N., Martinez-Coria, H., Fisher, A., & LaFerla, F. M. (2006) · Neuron · doi:10.1016/j.neuron.2006.01.020 · Cited by 417 · see citing works
Muscarinic acetylcholine receptors as CNS drug targets
Langmead, C. J., Watson, J. M., & Reavill, C. (2007) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2007.09.009 · Cited by 413 · see citing works
The synaptic organization of the brain
Precht, W. (1976) · Neuroscience · doi:10.1016/0306-4522(76)90053-1 · Cited by 399 · see citing works
Miyakawa, T., Yamada, M., Duttaroy, A., & Wess, J. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-14-05239.2001 · Cited by 366 · see citing works
The Biochemical Basis of Neuropharmacology
(1997) · Biomedicine & Pharmacotherapy · doi:10.1016/s0753-3322(97)89442-5 · Cited by 328 · see citing works
Sur, C., Mallorga, P. J., Wittmann, M., Jacobson, M. A., Pascarella, D. M., Williams, J. B., Brandish, P. E., Pettibone, D. J., Scolnick, E. M., & Conn, P. J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1835612100 · Cited by 295 · see citing works
Self-citationGerber, D., Sotnikova, T. D., Gainetdinov, R., Huang, S., Caron, M., & Tonegawa, S. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.261583798 · Cited by 282 · see citing works
Anticholinergics for symptomatic management of Parkinson´s disease
Katzenschlager, R., Sampaio, C. M., Costa, J. N., et al. (2002) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd003735 · Cited by 259 · see citing works
Muscarinic Acetylcholine Receptors
Ishii, M., & Kurachi, Y. (2006) · Current Pharmaceutical Design · doi:10.2174/138161206778522056 · Cited by 253 · see citing works
Jones, C. K., Brady, A. E., Davis, A. A., Xiang, Z., Bubser, M., Tantawy, M. N., Kane, A. S., Bridges, T. M., Kennedy, J. P., Bradley, S. R., et al. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1850-08.2008 · Cited by 248 · see citing works
Self-citationAllosteric modulation of the muscarinic M 4 receptor as an approach to treating schizophrenia
Chan, W. Y., McKinzie, D. L., Bose, S., Mitchell, S. N., Witkin, J. M., Thompson, R. C., Christopoulos, A., Lazareno, S., Birdsall, N. J. M., Bymaster, F. P., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0800567105 · Cited by 235 · see citing works
Therapeutic Opportunities for Muscarinic Receptors in the Central Nervous System
Felder, C. C., Bymaster, F. P., Ward, J. S., & DeLapp, N. W. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm990607u · Cited by 235 · see citing works
Jakubík, J., Bačáková, L., El‐Fakahany, E. E., et al. (1997) · Molecular Pharmacology · doi:10.1124/mol.52.1.172 · Cited by 230 · see citing works
A Family of Highly Selective Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5
O’Brien, J. A., Lemaire, W., Chen, T., Chang, R. S. L., Jacobson, M. A., Ha, S., Lindsley, C. W., Schaffhauser, H., Sur, C., Pettibone, D. J., et al. (2003) · Molecular Pharmacology · doi:10.1124/mol.64.3.731 · Cited by 209 · see citing works
Self-citationBrady, A. E., Jones, C. K., Bridges, T. M., Kennedy, J. P., Thompson, A. D., Heiman, J. U., Breininger, M. L., Gentry, P. R., Yin, H., Jadhav, S. B., et al. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.140350 · Cited by 204 · see citing works
Self-citationDiscovery of an Ectopic Activation Site on the M1Muscarinic Receptor
Spalding, T. A., Trotter, C., Skjærbæk, N., Messier, T., Currier, E. A., Burstein, E. S., Li, D., Hacksell, U., & Brann, M. R. (2002) · Molecular Pharmacology · doi:10.1124/mol.61.6.1297 · Cited by 193 · see citing works
Neuropsychiatric symptoms in the dementias
Assal, F., & Cummings, J. L. (2002) · Current Opinion in Neurology · doi:10.1097/00019052-200208000-00007 · Cited by 180 · see citing works
Bymaster, F. P., Carter, P. A., Yamada, M., Gomeza, J., Wess, J., Hamilton, S. E., Nathanson, N. M., McKinzie, D. L., & Felder, C. C. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02588.x · Cited by 167 · see citing works
Bullock, R. M., & Cameron, A. (2002) · Current Medical Research and Opinion · doi:10.1185/030079902125000813 · Cited by 161 · see citing works
An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission
Shirey-Rice, J. K., Xiang, Z., Orton, D., Brady, A. E., Johnson, K. A., Williams, R. D., Ayala, J. E., Rodriguez, A. L., Wess, J., Weaver, D., et al. (2007) · Nature Chemical Biology · doi:10.1038/nchembio.2007.55 · Cited by 161 · see citing works
Self-citationXanomeline and the Antipsychotic Potential of Muscarinic Receptor Subtype Selective Agonists
Mirza, N. R., Peters, D., & Sparks, R. G. (2003) · CNS Drug Reviews · doi:10.1111/j.1527-3458.2003.tb00247.x · Cited by 155 · see citing works
Marlo, J. E., Niswender, C. M., Days, E., Bridges, T. M., Xiang, Y., Rodriguez, A. L., Shirey-Rice, J. K., Brady, A. E., Nalywajko, T., Luo, Q., et al. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.052886 · Cited by 146 · see citing works
Self-citationMarino, M. J., & Conn, P. J. (2002) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1568007023339544 · Cited by 134 · see citing works
Self-citationCharacterization of a CNS penetrant, selective M1muscarinic receptor agonist, 77‐LH‐28‐1
Langmead, C. J., Austin, N. E., Branch, C. L., Brown, J. T., Buchanan, K. A., Davies, C. H., Forbes, I. T., Fry, V. A. H., Hagan, J. J., Herdon, H. J., et al. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.152 · Cited by 132 · see citing works
Muscarinic acetylcholine receptor
Heilbronn, E., & Bartfai, T. (1978) · Progress in Neurobiology · doi:10.1016/0301-0082(78)90011-4 · Cited by 129 · see citing works
Lazareno, S., Gharagozloo, P., Kuonen, D. R., Popham, A., & Birdsall, N. J. M. (1998) · Molecular Pharmacology · doi:10.1124/mol.53.3.573 · Cited by 125 · see citing works
Therapeutic Strategies for Alzheimer’s Disease
Barten, D. M., & Albright, C. F. (2008) · Molecular Neurobiology · doi:10.1007/s12035-008-8031-2 · Cited by 122 · see citing works
Elucidating the role of muscarinic receptors in psychosis
Felder, C. C., Porter, A. C., Skillman, T. L., Zhang, L., Bymaster, F. P., Nathanson, N. M., Hamilton, S. E., Gomeza, J., Wess, J., & McKinzie, D. L. (2001) · Life Sciences · doi:10.1016/s0024-3205(01)01059-1 · Cited by 120 · see citing works
Bodick, N. C., Offen, W., Shannon, H. E., Satterwhite, J. H., Lucas, R., van Lier, R., & Paul, S. M. (1997) · PubMed · Cited by 113 · see citing works
Lazareno, S., Doležal, V., Popham, A., & Birdsall, N. J. M. (2004) · Molecular Pharmacology · doi:10.1124/mol.65.1.257 · Cited by 104 · see citing works
Chen, Y., Goudet, C., Pin, J., & Conn, P. J. (2007) · Molecular Pharmacology · doi:10.1124/mol.107.040097 · Cited by 96 · see citing works
Self-citationFisher, A. (2008) · Neurodegenerative Diseases · doi:10.1159/000113712 · Cited by 87 · see citing works
Sharma, S., Rodriguez, A. L., Conn, P. J., & Lindsley, C. W. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.05.091 · Cited by 86 · see citing works
Self-citationFawzi, A. B., Macdonald, D., Benbow, L. L., Smith-Torhan, A., Zhang, H., Weig, B. C., Ho, G., Tulshian, D., Linder, M. E., & Graziano, M. P. (2001) · Molecular Pharmacology · doi:10.1016/s0026-895x(24)12353-x · Cited by 82 · see citing works
The efficacy of cholinesterase inhibitors in treating the behavioural symptoms of dementia.
Rösler, M. (2002) · PubMed · Cited by 70 · see citing works
Kaufer, D. (1998) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000051193 · Cited by 64 · see citing works
The ABC of Alzheimer's Disease: Behavioral Symptoms and Their Treatment
Grossberg, G. T. (2002) · International Psychogeriatrics · doi:10.1017/s1041610203008652 · Cited by 57 · see citing works
Thomas, R. L., Mistry, R., Langmead, C. J., et al. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.141788 · Cited by 56 · see citing works
Lebon, G., Langmead, C. J., Tehan, B. G., et al. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.050963 · Cited by 51 · see citing works
Lanzafame, A. A., & Christopoulos, A. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.060590 · Cited by 49 · see citing works
Cholinergic Agonists and the Treatment of Alzheimers Disease
Messer, W. S. (2002) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026024607553 · Cited by 43 · see citing works
Bridges, T. M., Brady, A. E., Kennedy, J. P., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.09.023 · Cited by 38 · see citing works
Miller, N., Daniels, R. N., Bridges, T. M., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.09.032 · Cited by 29 · see citing works
Treating Alzheimer's Disease With Cholinesterase Inhibitors: What Have We Learned So Far?
Feldman, H. (2002) · International Psychogeriatrics · doi:10.1017/s1041610203008639 · Cited by 9 · see citing works
Ray, W. J., Seager, M. A., Ma, L., et al. (2008) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2008.05.2375 · Cited by 4 · see citing works
P4‐332: In vivo pharmacodynamic effects of BQCA, a novel selective allosteric M1 receptor modulator
Wittmann, M., Xu, G., Pearson, M. S., et al. (2008) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2008.05.2402 · Cited by 3 · see citing works
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Wallace, T. L., Ballard, T. M., Pouzet, B., Riedel, W. J., & Wettstein, J. G. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.03.022 · Cited by 127 · see citing works
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Self-citation
- Authors
- Conn, P. J., Jones, C. K., & Lindsley, C. W.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Conn, P. Jeffrey
- Venue
- Trends in Pharmacological Sciences
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 30
- Issue
- 3
- Pages
- 148-155
- ISSN
- 0165-6147 (ISSN-L)
- PMC
- PMC2907736
- OpenAlex
- W2087372220
- Cited by
- 286
- References
- 56
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 11 · 2023: 9 · 2022: 10 · 2021: 14 · 2020: 9 · 2019: 15 · 2018: 14 · 2017: 14 · 2016: 12 · 2015: 16 · 2014: 23 · 2013: 26 · 2012: 31
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in Pharmacological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (U54MH084659, R01MH082867, R01MH073676)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- muscarinic receptors, allosteric modulators, subtype-selective agonists, M1 muscarinic receptor, M4 muscarinic receptor, Alzheimer's disease, schizophrenia, psychosis, cognitive impairment, central nervous system disorders
- MeSH terms
- Allosteric Regulation, Alzheimer Disease, Animals, Mental Disorders, Central Nervous System Agents, Humans, Receptors, Muscarinic, Schizophrenia, Antipsychotic Agents, Muscarinic Agonists, Muscarinic Antagonists, Receptor, Muscarinic M4, Receptor, Muscarinic M1
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