A large body of evidence indicates that the Ml muscarinic acetylcholine receptors (mAChRs) play a key role in memory, learning, and control of movement. Consequently, changes in Ml levels and activity have been implicated in pathophysiology of many CNS diseases including Alzheimer's disease. Schizophrenia, and Parkinson's disease. These findings provide a rational basis for the development of novel muscarinic agents that target Ml receptors. Unfortunately, previous compounds developed to selectively activate Ml have failed in clinical development due to lack of true specificity for Ml and adverse effects associated with activation of other mAChR subtypes. To overcome this obstacle, several types of muscarinic agents that target Ml receptors through ectopic sites topographically distinct from that of the orthosteric binding site have been generated. These novel allosteric agents include ectopic agonists TBPB and VU08184670 (AK2) as well as positive allosteric modulator (PAM) VU0238386 (BQCA). Each of these compounds show exquisite subtype selectivity and thus may be novel therapeutic approaches for treatment of symptoms associated with CNS diseases. Interestingly, TBPB, VU08184670 (AK2), and VU0238386 (BQCA) may also have differential effects on different Ml-mediated signaling pathways. This type of ligand-biased agonism is a characteristic of many ligands where they preferentially stimulate a certain repertoire of a receptor's activities. The preferential activation of a subset of a receptor's responses may be beneficial for combating negative symptoms associated with CNS disorders, as they might activate certain cellular responses without activating unneeded ancillary responses. In this proposal, I will use imaging assays to measure M1- mediated generation of IP3 production and p-arrestin recruitment in real time to determine if allosteric agents differentially regulate coupling of Ml receptors to different signaling pathways. I will also use electrophysiology in brain slices to determine if allosteric agents cause persistent Ml-mediated potentiation of NMDA currents. These proposed studies will allow us to ascertain whether allosteric agents elicit unique cellular response profiles when compared to orhtosteric agonists. More importantly, they will allow us to rigorously test the hypothesis that allosteric agents induce ligand-biased signaling at Ml that may be useful for improving therapies for patients suffering from a CNS disorders such as Alzheimer's and Parkinson's disease.
|Digby, Gregory J; Noetzel, Meredith J; Bubser, Michael et al. (2012) Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models. J Neurosci 32:8532-44|
|Digby, Gregory J; Utley, Thomas J; Lamsal, Atin et al. (2012) Chemical modification of the M(1) agonist VU0364572 reveals molecular switches in pharmacology and a bitopic binding mode. ACS Chem Neurosci 3:1025-36|