TY - JOUR T1 - Novel Selective Allosteric Activator of the M<sub>1</sub> Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats JF - The Journal of Neuroscience JO - J. Neurosci. SP - 10422 LP - 10433 DO - 10.1523/JNEUROSCI.1850-08.2008 VL - 28 IS - 41 AU - Carrie K. Jones AU - Ashley E. Brady AU - Albert A. Davis AU - Zixiu Xiang AU - Michael Bubser AU - Mohammed Noor Tantawy AU - Alexander S. Kane AU - Thomas M. Bridges AU - J. Phillip Kennedy AU - Stefania R. Bradley AU - Todd E. Peterson AU - M. Sib Ansari AU - Ronald M. Baldwin AU - Robert M. Kessler AU - Ariel Y. Deutch AU - James J. Lah AU - Allan I. Levey AU - Craig W. Lindsley AU - P. Jeffrey Conn Y1 - 2008/10/08 UR - http://www.jneurosci.org/content/28/41/10422.abstract N2 - Recent studies suggest that subtype-selective activators of M1/M4 muscarinic acetylcholine receptors (mAChRs) may offer a novel approach for the treatment of psychotic symptoms associated with schizophrenia and Alzheimer's disease. Previously developed muscarinic agonists have provided clinical data in support of this hypothesis, but failed in clinical development because of a lack of true subtype specificity and adverse effects associated with activation of other mAChR subtypes. We now report characterization of a novel highly selective agonist for the M1 receptor with no agonist activity at any of the other mAChR subtypes, termed TBPB [1-(1′-2-methylbenzyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one]. Mutagenesis and molecular pharmacology studies revealed that TBPB activates M1 through an allosteric site rather than the orthosteric acetylcholine binding site, which is likely critical for its unprecedented selectivity. Whole-cell patch-clamp recordings demonstrated that activation of M1 by TBPB potentiates NMDA receptor currents in hippocampal pyramidal cells but does not alter excitatory or inhibitory synaptic transmission, responses thought to be mediated by M2 and M4. TBPB was efficacious in models predictive of antipsychotic-like activity in rats at doses that did not produce catalepsy or peripheral adverse effects of other mAChR agonists. Finally, TBPB had effects on the processing of the amyloid precursor protein toward the non-amyloidogenic pathway and decreased Aβ production in vitro. Together, these data suggest that selective activation of M1 may provide a novel approach for the treatment of symptoms associated with schizophrenia and Alzheimer's disease. ER -