An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.
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.
Jana K
JK
Shirey
Zixiu
Z
Xiang
Darren
D
Orton
Ashley E
AE
Brady
Kari A
KA
Johnson
Richard
R
Williams
Jennifer E
JE
Ayala
Alice L
AL
Rodriguez
Jürgen
J
Wess
David
D
Weaver
Colleen M
CM
Niswender
P Jeffrey
PJ
Conn
D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D018721:Muscarinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D043588:Receptor, Muscarinic M4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects*
D008024:Ligands; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043588:Receptor, Muscarinic M4; D054852:Small Molecule Libraries; D002118:Calcium