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Synthesis and Biological Evaluation of Pyrroloindolines as Positive Allosteric Modulators of the α1β2γ2 GABA_A Receptor.

ABSTRACT: γ-Aminobutyric acid type A (GABA_A) 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 GABA_A 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 GABA_A 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.

SUBMITTER: Blom AEM

PROVIDER: S-EPMC7667864 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Synthesis and Biological Evaluation of Pyrroloindolines as Positive Allosteric Modulators of the α1β2γ2 GABAA Receptor.

Blom Annet E M AEM Su Justin Y JY Repka Lindsay M LM Reisman Sarah E SE Dougherty Dennis A DA

ACS medicinal chemistry letters 20200915 11

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 o ...[more]

PMID: 33214830

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