Article abstract
Nature Chemical Biology 4, 42 - 50 (2008)
Published online: 2 December 2007 | doi:10.1038/nchembio.2007.55
An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission
Jana K Shirey1,5, Zixiu Xiang1,5, Darren Orton2,3, Ashley E Brady1, Kari A Johnson1, Richard Williams2,3, Jennifer E Ayala1, Alice L Rodriguez1,2, Jürgen Wess4, David Weaver1,2, Colleen M Niswender1,2 & P Jeffrey Conn1,2
Abstract
Muscarinic acetylcholine receptors (mAChRs) provide viable targets for the treatment of multiple central nervous system disorders. We have used cheminformatics and medicinal chemistry to develop new, highly selective M4 allosteric potentiators. VU10010, the lead compound, potentiates the M4 response to acetylcholine 47-fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for acetylcholine and coupling to G proteins. Whole-cell patch clamp recordings revealed that selective potentiation of M4 with VU10010 increases carbachol-induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU10010 and was absent in M4 knockout mice. Selective regulation of excitatory transmission by M4 suggests that targeting of individual mAChR subtypes could be used to differentially regulate specific aspects of mAChR modulation of function in this important forebrain structure.
- Department of Pharmacology, Vanderbilt Program in Drug Discovery, 23rd Avenue South at Pierce, Nashville, Tennessee 37232-6600, USA.
- Vanderbilt Institute for Chemical Biology, 802 Robinson Research Building, Nashville, Tennessee 37232, USA.
- Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Station B 351822, Nashville, Tennessee 37235, USA.
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 8A, Room B1A-05, 8 Center Drive MSC 0810, Bethesda, Maryland 20892-0810, USA.
- These authors contributed equally to this work.
Correspondence to: P Jeffrey Conn1,2 e-mail: jeff.conn@vanderbilt.edu
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