Discovery of Selective Allosteric Modulators of Muscarinic M1 Receptors for the Treatment of Alzheimer’s Disease
Bill Shipe,
Research Fellow
Merck Research Labs
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Abstract: Allosteric modulation of the muscarinic M1 receptor is being explored as a means to overcome the cognitive deficits caused by the degeneration of the cholinergic system in patients with Alzheimer’s Disease (AD). While currently known agonists of M1 do provide cognitive benefit, they exhibit little or no selectivity over other muscarinic receptor subtypes, resulting in intolerable side effects. Allosteric modulation of M1 is utilized as a tactic for achieving subtype selectivity.
A quinolone lead was identified from an HTS screen as an allosteric modulator of the muscarinic M1 receptor, and demonstrates M1 receptor-subtype selectivity and 15-fold potentiation of acetylcholine. An iterative analog library strategy was employed in the search for other quinolone allosteric modulators of M1 with improved potency and pharmacokinetic properties.
Presenter Biography: Bill was born in Pittsburgh, PA in 1976 and grew up in nearby Murrysville, PA. He received his B. S. degree in Chemistry with a minor in Mathematics from Penn State University, where he performed undergraduate research with Professor Raymond L. Funk. In 1999, he began his graduate studies in synthetic organic chemistry at The Scripps Research Institute in La Jolla, CA. Under the direction of Professor E. J. Sorensen, he completed enantioselective total syntheses of the diterpene natural products guanacastepene A and E, spent 2003-2004 at Princeton University as a visiting graduate student, and obtained his Ph. D. degree from Scripps in 2004. He then began employment at Merck & Co., Inc in West Point, PA in the Department of Medicinal Chemistry, where he has been engaged in drug discovery efforts on various neuroscience and antiviral programs.
Reading List: 1. Verhoeff, NP. "Acetylcholinergic neurotransmission and the beta-amyloid cascade: implications for Alzheimer's disease." Expert Rev Neurotherapeutics 2005, 5, 277-284.
2. Terry, AV; Buccafusco, JJ. "The cholinergic hypothesis of Age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development." J Pharmacol Exp Ther 2003, 306, 821-827.
3. Christopoulos, A. "Allosteric binding sites on cell-surface receptors: novel targets for drug discovery." Nat Rev Drug Discov 2002, 1, 198-210.
4. Wess, J. "Allosteric binding sites on muscarinic acetylcholine receptors." Mol Pharmacol 2005, 68, 1506-1509.
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