Abstract:
:γ-Aminobutyric acid type A (GABAA) receptors are key mediators of central inhibitory neurotransmission and have been implicated in several disorders of the central nervous system. Some positive allosteric modulators (PAMs) of this receptor provide great therapeutic benefits to patients. However, adverse effects remain a challenge. Selective targeting of GABAA receptors could mitigate this problem. Here, we describe the synthesis and functional evaluation of a novel series of pyrroloindolines that display significant modulation of the GABAA receptor, acting as PAMs. We found that halogen incorporation at the C5 position greatly increased the PAM potency relative to the parent ligand, while substitutions at other positions generally decreased potency. Mutagenesis studies suggest that the binding site lies at the top of the transmembrane domain.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Blom AEM,Su JY,Repka LM,Reisman SE,Dougherty DAdoi
10.1021/acsmedchemlett.0c00340subject
Has Abstractpub_date
2020-09-15 00:00:00pages
2204-2211issue
11issn
1948-5875journal_volume
11pub_type
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