Abstract
Targeting allosteric sites of the M 1 muscarinic acetylcholine receptor (mAChR) is an enticing approach to overcome the lack of receptor subtype selectivity observed with orthosteric ligands. This is a promising strategy for obtaining novel therapeutics to treat cognitive deficits observed in Alzheimer's disease and schizophrenia, while reducing the peripheral side effects such as seen in the current treatment regimes, which are non-subtype selective. We previously described compound 2, the first positive allosteric modulator (PAM) of the M 1 mAChR based on a 6-phenylpyrimidin-4-one scaffold, which has been further developed in this study. Herein, we present the synthesis, characterization, and pharmacological evaluation of a series of 6-phenylpyrimidin-4-ones with modifications to the 4-(1-methylpyrazol-4-yl)benzyl pendant. Selected compounds, BQCA, 1, 2, 9i, 13, 14b, 15c, and 15d, were further profiled in terms of their allosteric affinity, cooperativity with acetylcholine (ACh), and intrinsic efficacy. Additionally, 2 and 9i were tested in mouse primary cortical neurons, displaying various degrees of intrinsic agonism and potentiation of the acetylcholine response. Overall, the results suggest that the pendant moiety is important for allosteric binding affinity and the direct agonistic efficacy of the 6-phenylpyrimidin-4-one based M 1 mAChR PAMs.
| Original language | English |
|---|---|
| Pages (from-to) | 1099-1114 |
| Number of pages | 16 |
| Journal | ACS Chemical Neuroscience |
| Volume | 10 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 20 Mar 2019 |
Keywords
- Alzheimer's disease
- BQCA
- M muscarinic acetylcholine receptor
- positive allosteric modulator
- pyrimidinones
- schizophrenia
Cite this
}
6-Phenylpyrimidin-4-ones as Positive Allosteric Modulators at the M1 mAChR : The Determinants of Allosteric Activity. / Jorg, Manuela Therese; van der Westhuizen, Emma T; Khajehali, Elham; Burger, Wessel Alexander Christian; White, Jonathan; Choy, Kwok Ho Christopher; Tobin, Andrew B.; Sexton, Patrick Michael; Valant, Celine; Capuano, Benvenuto; Christopoulos, Arthur; Scammells, Peter John.
In: ACS Chemical Neuroscience, Vol. 10, No. 3, 20.03.2019, p. 1099-1114.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - 6-Phenylpyrimidin-4-ones as Positive Allosteric Modulators at the M1 mAChR
T2 - The Determinants of Allosteric Activity
AU - Jorg, Manuela Therese
AU - van der Westhuizen, Emma T
AU - Khajehali, Elham
AU - Burger, Wessel Alexander Christian
AU - White, Jonathan
AU - Choy, Kwok Ho Christopher
AU - Tobin, Andrew B.
AU - Sexton, Patrick Michael
AU - Valant, Celine
AU - Capuano, Benvenuto
AU - Christopoulos, Arthur
AU - Scammells, Peter John
PY - 2019/3/20
Y1 - 2019/3/20
N2 - Targeting allosteric sites of the M 1 muscarinic acetylcholine receptor (mAChR) is an enticing approach to overcome the lack of receptor subtype selectivity observed with orthosteric ligands. This is a promising strategy for obtaining novel therapeutics to treat cognitive deficits observed in Alzheimer's disease and schizophrenia, while reducing the peripheral side effects such as seen in the current treatment regimes, which are non-subtype selective. We previously described compound 2, the first positive allosteric modulator (PAM) of the M 1 mAChR based on a 6-phenylpyrimidin-4-one scaffold, which has been further developed in this study. Herein, we present the synthesis, characterization, and pharmacological evaluation of a series of 6-phenylpyrimidin-4-ones with modifications to the 4-(1-methylpyrazol-4-yl)benzyl pendant. Selected compounds, BQCA, 1, 2, 9i, 13, 14b, 15c, and 15d, were further profiled in terms of their allosteric affinity, cooperativity with acetylcholine (ACh), and intrinsic efficacy. Additionally, 2 and 9i were tested in mouse primary cortical neurons, displaying various degrees of intrinsic agonism and potentiation of the acetylcholine response. Overall, the results suggest that the pendant moiety is important for allosteric binding affinity and the direct agonistic efficacy of the 6-phenylpyrimidin-4-one based M 1 mAChR PAMs.
AB - Targeting allosteric sites of the M 1 muscarinic acetylcholine receptor (mAChR) is an enticing approach to overcome the lack of receptor subtype selectivity observed with orthosteric ligands. This is a promising strategy for obtaining novel therapeutics to treat cognitive deficits observed in Alzheimer's disease and schizophrenia, while reducing the peripheral side effects such as seen in the current treatment regimes, which are non-subtype selective. We previously described compound 2, the first positive allosteric modulator (PAM) of the M 1 mAChR based on a 6-phenylpyrimidin-4-one scaffold, which has been further developed in this study. Herein, we present the synthesis, characterization, and pharmacological evaluation of a series of 6-phenylpyrimidin-4-ones with modifications to the 4-(1-methylpyrazol-4-yl)benzyl pendant. Selected compounds, BQCA, 1, 2, 9i, 13, 14b, 15c, and 15d, were further profiled in terms of their allosteric affinity, cooperativity with acetylcholine (ACh), and intrinsic efficacy. Additionally, 2 and 9i were tested in mouse primary cortical neurons, displaying various degrees of intrinsic agonism and potentiation of the acetylcholine response. Overall, the results suggest that the pendant moiety is important for allosteric binding affinity and the direct agonistic efficacy of the 6-phenylpyrimidin-4-one based M 1 mAChR PAMs.
KW - Alzheimer's disease
KW - BQCA
KW - M muscarinic acetylcholine receptor
KW - positive allosteric modulator
KW - pyrimidinones
KW - schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=85063237863&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.8b00613
DO - 10.1021/acschemneuro.8b00613
M3 - Article
VL - 10
SP - 1099
EP - 1114
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 3
ER -