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Muscarinic Receptor Agonists: Not Created Equal

11 July 2012. Agonists of the M1 muscarinic acetylcholine receptor show promise as schizophrenia drug targets. However, in a new study published June 20 in the Journal of Neuroscience, P. Jeffrey Conn of Vanderbilt University in Nashville, Tennessee, and colleagues support the idea that substantial variability is present among different agonists, and that these differences can alter their therapeutic potential.

Current pharmacological treatments for schizophrenia leave a lot to be desired. Antipsychotic drugs ameliorate or eliminate positive symptoms in most patients, but leave negative and cognitive symptoms largely unaffected. Given that the latter are the best predictor of functional outcome, developing new treatments for schizophrenia is of paramount importance. Recently, muscarinic acetylcholine receptors have been gaining momentum as viable drug targets for cognitive disorders including schizophrenia and Alzheimer’s disease (Bolbecker and Shekhar, 2012; see SRF related news story; SRF news story). For example, M1 receptors are known to be important in various domains of cognition, and a pilot study of the M1- and M4-selective agonist xanomeline found a reduction in positive and negative symptoms, as well as cognitive improvements, in schizophrenia (Shekhar et al., 2008).

Lack of muscarinic agonists with selectivity for individual receptor subtypes has hampered past attempts at drug development. However, compounds that exhibit very high selectivity for single subtypes, such as M1, and particularly for allosteric sites away from the main ligand binding site, have recently been developed. M1 agonists are known to activate a variety of signaling pathways involving calcium, β-arrestin, and extracellular regulated signal kinase (ERK), and recent data suggest that different allosteric M1 agonists may activate different signaling pathways (Thomas et al., 2008). Thus, Conn and colleagues reasoned that if specific drugs activate only some of the M1-mediated responses, the effects of individual drugs, and their therapeutic potential, may vary widely. In the present study, the researchers examined this idea by comparing the signaling, electrophysiological, and behavioral properties of their two recently developed, highly selective M1 allosteric agonists—VU0357017 and VU0364572 (Lebois et al., 2010; Lebois et al., 2011).

Using non-neuronal cell lines, first author Gregory Digby and colleagues found that both agonists increased calcium mobilization and activated ERK1/2 phosphorylation, but neither had a significant effect on β-arrestin recruitment. Since both agonists, especially VU0357017, exhibited relatively weak effects on calcium and phosphorylated ERK1/2, the researchers hypothesized that the drugs may be partial agonists, and thus would behave differently in systems with low receptor expression. In fact, both drugs did behave as partial agonists, though VU0364572 had a stronger effect on both calcium mobilization and ERK1/2 phosphorylation.

Digby and colleagues next probed the physiological and behavioral function of their agonists. Using rat hippocampal slices, they examined the effect on synaptic plasticity, thought to underlie the memory-enhancing effects of M1 activation. Both drugs induced long-term potentiation in hippocampal slices (similar to what has been reported for other M1 agonists), though only VU0364572 induced long-term depression. To examine the behavioral correlates of these electrophysiological studies, the researchers assessed hippocampal-dependent cognitive functioning using the Morris water maze, an assay of spatial learning and memory, and contextual fear conditioning, another measure of learning. Although intraperitoneal injection of VU0357017 had no effect on water maze performance, injection of VU0364572 produced enhanced performance. Both drugs improved the acquisition of contextual fear.

Next, the researchers turned to the medial prefrontal cortex, a brain region implicated in the working memory and learning improvements seen with M1 agonists. A prior study of an M1 agonist from Conn’s group had found increased excitatory postsynaptic current (EPSC) activity in the medial prefrontal cortex and improved reversal learning (Shirey et al. 2009). In the current study, however, neither agonist affected the inter-event interval of firing, indicating no change in single EPSC frequency. Reversal learning was not measured. Thus, the lack of strong effects in medial prefrontal cortex with the new agents buttresses the idea of variability among different M1 agonists.

Conn’s group also assessed the ability of the agonists to reverse amphetamine-induced hyperlocomotion, thought to be an effect of M1 receptors on dopamine neurotransmission in the striatum and hypothesized to be the mechanism underlying the antipsychotic effect of xanomeline. Unfortunately, unlike a previous report from his group, neither agonist demonstrated an effect on hyperlocomotion, and exhibited only weak effects on the excitability of medium spiny neurons in the striatum, suggesting that these drugs will have limited antipsychotic properties.

Taken together, the results of the current study suggest that different allosteric agonists can have distinct effects on M1-mediated responses that produce varying therapeutic effects. As noted by the authors in the discussion, these data have implications for future drug development. “The present findings suggest that reliance on a streamlined strategy of optimizing with a single readout of M1 function could yield compounds that may not have the desired effects…. Also, measuring physiological effects of advanced compounds in multiple CNS systems is important to reduce the risk of inadvertently advancing drug candidates that have more restricted CNS actions.”—Allison A. Curley.

Digby GJ, Noetzel MJ, Bubser M, Utley TJ, Walker AG, Byun NE, Lebois EP, Xiang Z, Sheffler DJ, Cho HP, Davis AA, Nemirovsky NE, Mennenga SE, Camp BW, Bimonte-Nelson HA, Bode J, Italiano K, Morrison R, Daniels JS, Niswender CM, Olive MF, Lindsley CW, Jones CK, Conn PJ. Novel Allosteric Agonists of M1 Muscarinic Acetylcholine Receptors Induce Brain Region-Specific Responses That Correspond with Behavioral Effects in Animal Models. J Neurosci . 2012 Jun 20 ; 32(25):8532-8544. Abstract

Comments on News and Primary Papers
Comment by:  Bryan Roth, SRF Advisor
Submitted 15 July 2012 Posted 16 July 2012
  I recommend the Primary Papers

This is an interesting and important paper which serves as...  Read more

View all comments by Bryan Roth

Comment by:  Rick Neubig
Submitted 19 July 2012 Posted 20 July 2012

This is a very useful paper, but it is worth pointing out...  Read more

View all comments by Rick Neubig

Comment by:  Anantha ShekharAmanda Bolbecker
Submitted 27 July 2012 Posted 27 July 2012

The discovery of M1 allosteric agonists caused a great...  Read more

View all comments by Anantha Shekhar
View all comments by Amanda Bolbecker

Comment by:  Bryan Roth, SRF Advisor
Submitted 1 August 2012 Posted 1 August 2012

Regarding the comment by Rick Neubig: while it could be...  Read more

View all comments by Bryan Roth
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