An allosteric potentiator of M₄ mAChR modulates hippocampal synaptic transmission.

<p>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 M<sub style="font-family: Verdana, arial, Helvetica, sans-serif; background-color: rgb(255, 255, 255);">4</sub> allosteric potentiators. VU10010, the lead compound, potentiates the M<sub style="font-family: Verdana, arial, Helvetica, sans-serif; background-color: rgb(255, 255, 255);">4</sub> 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 M<sub style="font-family: Verdana, arial, Helvetica, sans-serif; background-color: rgb(255, 255, 255);">4</sub> 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 M<sub style="font-family: Verdana, arial, Helvetica, sans-serif; background-color: rgb(255, 255, 255);">4</sub> knockout mice. Selective regulation of excitatory transmission by M<sub style="font-family: Verdana, arial, Helvetica, sans-serif; background-color: rgb(255, 255, 255);">4</sub> 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.</p>