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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):8532-44. PubMed Abstract

Comments on Paper and Primary News
Primary News: Muscarinic Receptor Agonists: Not Created Equal

Comment by:  Bryan Roth, SRF Advisor
Submitted 15 July 2012 Posted 16 July 2012
  I recommend this paper

This is an interesting and important paper which serves as a cautionary reminder regarding the potential activity of allosteric modulators to have "functionally selective" effects on GPCR signaling (Urban et al., 2007; Allen and Roth, 2011). Thus, it has been known for decades (see Urban et al., 2007, for review) that GPCR "agonists" and "antagonists" can activate distinct signaling pathways and that a drug can appear to be an "agonist" for one pathway and have "antagonist" activity at another. As we have recently suggested, such activity could have potentially therapeutic implications for schizophrenia and related disorders (Allen et al., 2011).

Although it has been recognized for some time that allosteric modulators of GPCR activity may also have functionally selective actions (Sheffler and Conn, 2008) in vitro, it was unknown if these...  Read more

View all comments by Bryan Roth

Primary News: Muscarinic Receptor Agonists: Not Created Equal

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

This is a very useful paper, but it is worth pointing out that there is really no evidence for "ligand bias" or "functional selectivity" of these compounds. The VU analogs are partial agonists but show no bias toward one signal pathway or another. The low ERK and α-arrestin signaling are due to the lower degree of receptor reserve for those two pathways and the requirement for more efficacious agonists to signal. The correlation of the in-vitro studies with the different in-vivo readouts does provide very important guidance for pharmacologists about what properties are needed for M1 agonists to produce different physiological effects. It doesn't, however, give any real information about "biased agonists."

View all comments by Rick Neubig

Primary News: Muscarinic Receptor Agonists: Not Created Equal

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

The discovery of M1 allosteric agonists caused a great deal of excitement because they act on the M1 receptor fairly exclusively. The new research by Digby et al. suggests that this newer class of compounds can influence very specific molecular signaling pathways initiated by M1 activation, and that these pathways mediate specific aspects of cognition. These findings could have profound effects on the development of novel therapeutic agents for cognitive impairments seen in schizophrenia and other severe neuropsychiatric disorders.

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View all comments by Amanda Bolbecker

Primary News: Muscarinic Receptor Agonists: Not Created Equal

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

Regarding the comment by Rick Neubig: while it could be argued that the paper does not provide "gold standard" pharmacological data for bona fide functional selectivity/stimulus bias, in fairness to the authors I provide their conclusions directly from the paper:

"Thus, the differential effects of these M1 agonists on CNS responses may reflect a combination of partial agonist activity that is impacted by differences in receptor reserve and by an inherent stimulus bias at M1 so that these compounds are not capable of fully activating some responses, even in systems in which the receptor is highly expressed…. Thus, different levels of M1 expression are likely to contribute to the differential responses to VU0357017 and VU0364572 observed in these studies. However, it was interesting to find that VU0357017 never achieved full efficacy in activation of ERK1/2 phosphorylation, even in cell lines with strong induction of M1 expression to levels that induced high receptor reserve in the calcium mobilization assay. Also, VU0357017 did not induce robust β-arrestin responses in...  Read more

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