. Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation. Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15950-5. PubMed.

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  1. The studies reported by Ray and coworkers represent a fundamental advance. They provide further evidence that it will be possible to develop highly selective activators of the M1 muscarinic receptor by targeting allosteric sites. Unlike recently discovered allosteric agonists of M1, i.e., TBPB, AC42, and 77-LH-28-1, BQCA is not an M1 agonist but an allosteric potentiator of responses of M1 to ACh. This is similar to other recently described allosteric potentiators of M1, M4, and M5, and may offer potential advantages as well as disadvantages relative to allosteric agonists. However, BQCA is the first M1 allosteric potentiator that has both exquisite selectivity and pharmacokinetic properties needed for use in studies in animal models that are relevant to Alzheimer disease. Thus, when combined with recently described highly selective systemically active M1 allosteric agonists, this provides the first set of tools to allow systematic studies aimed at determining the optimal properties of a drug that should be advanced as a clinical candidate for treatment of AD and other disorders. Also, a highly selective M1 antagonist as well as selective M4 and M5 allosteric potentiators have become available in the last year, which provide an unprecedented set of tools to allow major advances in this important area over the coming years.

    View all comments by P. Jeffrey Conn