July 17, 2012

Insights for neuroscience drug discovery

When discovering drugs for brain disorders, it’s important to test the candidates in multiple ways to avoid advancing those with restricted physiological effects.


Drugs that selectively activate the “M1” type of muscarinic acetylcholine receptor are being explored as new treatments for schizophrenia and other major brain disorders.

Jeffrey Conn, Lee E. Limbird Chair in Pharmacology, and colleagues have discovered novel M1 allosteric agonists, drugs that can “turn up” the activity of the M1 receptor. They now report that two of these compounds activate some – but not all – M1-regulated signaling pathways in cells. They further demonstrate that these drugs have robust effects in some brain areas, such as the hippocampus, but not in other brain regions, and that these differences correspond to behavioral effects in animal models. Both M1 agonists enhanced hippocampal-dependent cognitive functions, but did not exhibit antipsychotic activity in rats.

The studies in the June 20 Journal of Neuroscience offer new insights for M1 receptor-mediated responses and drug development. They emphasize the importance of measuring drug effects on multiple cellular signaling pathways and in multiple brain systems to avoid advancing drug candidates that have restricted physiological effects.

This research was supported by grants from the National Institute of Mental Health (MH084659, MH082867, MH087965, MH073676, MH087039, MH065215) and the National Institute of Neurological Disorders and Stroke (NS071746, NS065867) of the National Institutes of Health.

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