Selective positive allosteric modulator of M4 receptor (KB = 200 nM, α = 35); increases the potency of acetylcholine by 40-fold. Exhibits no effect at hM1/3/5 receptors and a small effect at hM2 (KB = 1 μM α = 3.7). Potentiates other full and partial orthosteric agonists, including Carbachol, Oxotremorine-M, and McN-A343. Does not affect binding of antagonist NMS. Active in vivo. Antipsychotic. α indicates the degree of allosteric enhancement when both orthosteric and allosteric sites are occupied (derived from the allosteric ternary complex model).
Leach et al (2010) Molecular mechanisms of action and in vivo validation of an M4 muscarinic acetylcholine receptor allosteric modulator with potential antipsychotic properties. Neuropsychopharmacology 35 855 PMID:19940843 |Huynh et al (2015) Synthesis and pharmacological evaluation of M4 muscarinic receptor positive allosteric modulators derived from VU10004. ACS Chem. Neurosci. 6 838 PMID:25857219 |Chan et al (2008) Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia Proc.Natl.Acad.Sci.U.S.A. 105 10978 PMID:18678919