| dc.description.abstract | Muscarinic acetylcholine receptors (mAChRs), specifically M1 and M4 subtypes, provide viable targets for the treatment of multiple central nervous system disorders. However, highly selective activators of either M1 or M4 have not been available, making it difficult to determine the in vivo effects of selective activation of these receptors. We have used cheminformatics and medicinal chemistry to develop new, highly selective M1 and M4 positive allosteric modulators (PAMs). VU10010 potentiated the functional M4 response to acetylcholine while having no activity at other mAChR subtypes. Whole-cell patch clamp recordings revealed that VU10010 increased carbachol-induced depression of transmission at excitatory but not inhibitory synapses at the Schaffer collateral-CA1 (SC-CA1) synapse in the hippocampus. Chemical optimization of VU10010 afforded two centrally penetrant analogs, VU0152099 and VU0152100, which are also potent, selective M4 PAMs. Interestingly, these compounds reversed amphetamine-induced hyperlocomotion in rats, a model that is predictive of clinical antipsychotic efficacy in humans.
A growing body of literature also supports M1 receptors as a viable target for treatment of disorders involving impaired cognitive function. Data in this thesis reports the molecular characterization of a novel compound, BQCA, which is a potent, highly selective PAM of the rat M1 receptor. BQCA induced a robust inward current and increased spontaneous EPSCs in mPFC layer V pyramidal cells, effects which were absent in acute slices from M1 receptor knockout mice. Furthermore, multiple single-unit recordings were obtained from the mPFC of rats which showed that BQCA increased firing of pyramidal cells in vivo. BQCA also restored discrimination reversal learning in a transgenic mouse model of AD and regulated non-amyloidogenic APP processing in vitro.
Together, these studies provide compelling evidence while M4 inhibits excitatory transmission at the SC-CA1 synapse, M1 receptor activation induces a dramatic excitation of PFC neurons. Newly developed highly selective ligands that activate or potentiate M1 and M4 provide exciting tools that will be useful in further delineating the individual roles of these receptors in the efficacy of drugs like acetyl cholinesterase inhibitors and xanomeline. | |
