Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats.
Recent studies suggest that subtype-selective activators of M(1)/M(4) 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 M(1) 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 M(1) 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 M(1) 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 M(2) and M(4). 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 Abeta production in vitro. Together, these data suggest that selective activation of M(1) may provide a novel approach for the treatment of symptoms associated with schizophrenia and Alzheimer's disease.
Jones
Carrie K
CK
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600, USA.
Brady
Ashley E
AE
Davis
Albert A
AA
Xiang
Zixiu
Z
Bubser
Michael
M
Tantawy
Mohammed Noor
MN
Kane
Alexander S
AS
Bridges
Thomas M
TM
Kennedy
J Phillip
JP
Bradley
Stefania R
SR
Peterson
Todd E
TE
Ansari
M Sib
MS
Baldwin
Ronald M
RM
Kessler
Robert M
RM
Deutch
Ariel Y
AY
Lah
James J
JJ
Levey
Allan I
AI
Lindsley
Craig W
CW
Conn
P Jeffrey
PJ
D000495:Allosteric Site / Q000502:physiology*; D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000819:agonists / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects; D014162:Transfection
C532626:1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo(d)imidazol-2-(3H)-one; D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D014150:Antipsychotic Agents; D001562:Benzimidazoles; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate