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The Journal of Neuroscience, October 8, 2008, 28(41):10422-10433; doi:10.1523/JNEUROSCI.1850-08.2008

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Neurobiology of Disease
Novel Selective Allosteric Activator of the M₁ Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats

Carrie K. Jones,^1,5 Ashley E. Brady,^1,5 Albert A. Davis,⁸ Zixiu Xiang,¹ Michael Bubser,³ Mohammed Noor Tantawy,⁶ Alexander S. Kane,¹ Thomas M. Bridges,¹ J. Phillip Kennedy,² Stefania R. Bradley,⁷ Todd E. Peterson,^4,6 M. Sib Ansari,^4,6 Ronald M. Baldwin,^4,6 Robert M. Kessler,⁴ Ariel Y. Deutch,^1,3 James J. Lah,⁸ Allan I. Levey,⁸ Craig W. Lindsley,^1,2,5 and P. Jeffrey Conn^1,5

Departments of ¹Pharmacology, ²Chemistry, ³Psychiatry, and ⁴Radiology and Radiological Sciences/PET Chemistry, ⁵Vanderbilt Program in Drug Discovery, and ⁶Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee 37232, ⁷ACADIA Pharmaceuticals, San Diego, California 92121, and ⁸Center for Neurodegenerative Disease and Department of Neurology, Emory University, Atlanta, Georgia 30322

Correspondence should be addressed to Dr. P. Jeffrey Conn, Director, Vanderbilt Program in Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center, 2220 Pierce Avenue, 1215 Light Hall, Nashville, TN 37232-6600. Email: jeff.conn{at}vanderbilt.edu

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.

Key words: TBPB; M₁ allosteric agonist; muscarinic acetylcholine receptors; schizophrenia; Alzheimer's disease; mAChR

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Received April 27, 2008; revised July 20, 2008; accepted July 30, 2008.

Correspondence should be addressed to Dr. P. Jeffrey Conn, Director, Vanderbilt Program in Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center, 2220 Pierce Avenue, 1215 Light Hall, Nashville, TN 37232-6600. Email: jeff.conn{at}vanderbilt.edu

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