PMID- 29701957
OWN - NLM
STAT- MEDLINE
DCOM- 20191211
LR  - 20191217
IS  - 1948-7193 (Electronic)
IS  - 1948-7193 (Linking)
VI  - 9
IP  - 9
DP  - 2018 Sep 19
TI  - A Novel M(1) PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying 
      Agonist Activity or Cholinergic Toxicity.
PG  - 2274-2285
LID - 10.1021/acschemneuro.8b00131 [doi]
AB  - Selective activation of the M(1) subtype of muscarinic acetylcholine receptor, 
      via positive allosteric modulation (PAM), is an exciting strategy to improve 
      cognition in schizophrenia and Alzheimer's disease patients. However, highly 
      potent M(1) ago-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender 
      excessive activation of M(1), leading to agonist actions in the prefrontal cortex 
      (PFC) that impair cognitive function, induce behavioral convulsions, and result 
      in other classic cholinergic adverse events (AEs). Here, we report a 
      fundamentally new and highly selective M(1) PAM, VU0486846. VU0486846 possesses 
      only weak agonist activity in M(1)-expressing cell lines with high receptor 
      reserve and is devoid of agonist actions in the PFC, unlike previously reported 
      ago-PAMs MK-7622, PF-06764427, and PF-06827443. Moreover, VU0486846 shows no 
      interaction with antagonist binding at the orthosteric acetylcholine (ACh) site 
      (e.g., neither bitopic nor displaying negative cooperativity with [(3)H]-NMS 
      binding at the orthosteric site), no seizure liability at high brain exposures, 
      and no cholinergic AEs. However, as opposed to ago-PAMs, VU0486846 produces 
      robust efficacy in the novel object recognition model of cognitive function. 
      Importantly, we show for the first time that an M(1) PAM can reverse the 
      cognitive deficits induced by atypical antipsychotics, such as risperidone. These 
      findings further strengthen the argument that compounds with modest in vitro M(1) 
      PAM activity (EC(50) > 100 nM) and pure-PAM activity in native tissues display 
      robust procognitive efficacy without AEs mediated by excessive activation of 
      M(1). Overall, the combination of compound assessment with recombinant in vitro 
      assays (mindful of receptor reserve), native tissue systems (PFC), and phenotypic 
      screens (behavioral convulsions) is essential to fully understand and evaluate 
      lead compounds and enhance success in clinical development.
FAU - Rook, Jerri M
AU  - Rook JM
FAU - Bertron, Jeanette L
AU  - Bertron JL
FAU - Cho, Hyekyung P
AU  - Cho HP
FAU - Garcia-Barrantes, Pedro M
AU  - Garcia-Barrantes PM
FAU - Moran, Sean P
AU  - Moran SP
AUID- ORCID: 0000-0001-7672-242X
FAU - Maksymetz, James T
AU  - Maksymetz JT
FAU - Nance, Kellie D
AU  - Nance KD
AUID- ORCID: 0000-0002-4396-9124
FAU - Dickerson, Jonathan W
AU  - Dickerson JW
FAU - Remke, Daniel H
AU  - Remke DH
FAU - Chang, Sichen
AU  - Chang S
FAU - Harp, Joel M
AU  - Harp JM
FAU - Blobaum, Anna L
AU  - Blobaum AL
FAU - Niswender, Colleen M
AU  - Niswender CM
FAU - Jones, Carrie K
AU  - Jones CK
FAU - Stauffer, Shaun R
AU  - Stauffer SR
FAU - Conn, P Jeffrey
AU  - Conn PJ
FAU - Lindsley, Craig W
AU  - Lindsley CW
AUID- ORCID: 0000-0003-0168-1445
LA  - eng
GR  - U19 MH106839/MH/NIMH NIH HHS/United States
GR  - R01 AG051626/AG/NIA NIH HHS/United States
GR  - U54 HD083211/HD/NICHD NIH HHS/United States
GR  - F31 MH114368/MH/NIMH NIH HHS/United States
GR  - R01 MH082867/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180508
PL  - United States
TA  - ACS Chem Neurosci
JT  - ACS chemical neuroscience
JID - 101525337
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Morpholines)
RN  - 0 (Pyrazoles)
RN  - 0 (VU0486846)
RN  - L6UH7ZF8HC (Risperidone)
SB  - IM
MH  - Allosteric Regulation
MH  - Animals
MH  - Antipsychotic Agents/toxicity
MH  - CHO Cells
MH  - Cognition/*drug effects
MH  - Cognitive Dysfunction/chemically induced/physiopathology
MH  - Conditioning, Psychological/*drug effects
MH  - Cricetulus
MH  - Exploratory Behavior/*drug effects
MH  - Fear
MH  - Mice
MH  - Morpholines/*pharmacology/toxicity
MH  - Prefrontal Cortex/*drug effects
MH  - Pyrazoles/*pharmacology/toxicity
MH  - Rats
MH  - Risperidone/toxicity
MH  - Seizures/chemically induced
PMC - PMC6146057
MID - NIHMS969828
OTO - NOTNLM
OT  - M1
OT  - ago-PAM
OT  - agonist
OT  - cognition
OT  - muscarinic acetylcholine receptor
OT  - positive allosteric modulator
OT  - schizophrenia
EDAT- 2018/04/28 06:00
MHDA- 2019/12/18 06:00
PMCR- 2019/09/19
CRDT- 2018/04/28 06:00
PHST- 2018/04/28 06:00 [pubmed]
PHST- 2019/12/18 06:00 [medline]
PHST- 2018/04/28 06:00 [entrez]
PHST- 2019/09/19 00:00 [pmc-release]
AID - 10.1021/acschemneuro.8b00131 [doi]
PST - ppublish
SO  - ACS Chem Neurosci. 2018 Sep 19;9(9):2274-2285. doi: 10.1021/acschemneuro.8b00131. 
      Epub 2018 May 8.