Synthesis and Pharmacological
Evaluation of Heterocyclic
Carboxamides: Positive Allosteric Modulators of the M1 Muscarinic
Acetylcholine Receptor with Weak Agonist Activity and Diverse Modulatory
Profiles
Version 2 2018-03-23, 20:47
Version 1 2018-03-23, 20:45
Posted on 2018-03-23 - 20:47
Targeting
allosteric sites at M1 muscarinic acetylcholine
receptors is a promising strategy for the treatment of Alzheimer’s
disease. Positive allosteric modulators not only may potentiate binding
and/or signaling of the endogenous agonist acetylcholine (ACh) but
also may possess direct agonist activity (thus referred to as PAM-agonists).
Recent studies suggest that PAM-agonists with robust intrinsic efficacy
are more likely to produce adverse effects in vivo. Herein we
present the synthesis and pharmacological evaluation of a series of
pyrrole-3-carboxamides with a diverse range of allosteric profiles.
We proposed structural modifications at top, core, or pendant moieties
of a prototypical molecule. Although generally there was a correlation
between the degree of agonist activity and the modulatory potency
of the PAMs, some derivatives displayed weak intrinsic efficacy yet
maintained strong allosteric modulation. We also identified molecules
with the ability to potentiate mainly the affinity or both affinity
and efficacy of ACh.
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Dallagnol, Juliana
C. C.; Khajehali, Elham; van der Westhuizen, Emma T.; Jörg, Manuela; Valant, Celine; Gonçalves, Alan G.; et al. (2018). Synthesis and Pharmacological
Evaluation of Heterocyclic
Carboxamides: Positive Allosteric Modulators of the M1 Muscarinic
Acetylcholine Receptor with Weak Agonist Activity and Diverse Modulatory
Profiles. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.7b01812
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AUTHORS (9)
JD
Juliana
C. C. Dallagnol
EK
Elham Khajehali
Ev
Emma T. van der Westhuizen
MJ
Manuela Jörg
CV
Celine Valant
AG
Alan G. Gonçalves
BC
Ben Capuano
AC
Arthur Christopoulos
PS
Peter J. Scammells