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

Blom, Annet E. M. and Su, Justin Y. and Repka, Lindsay M. and Reisman, Sarah E. and Dougherty, Dennis A. (2020) Synthesis and Biological Evaluation of Pyrroloindolines as Positive Allosteric Modulators of the α1β2γ2 GABA_A Receptor. ACS Medicinal Chemistry Letters, 11 (11). pp. 2204-2211. ISSN 1948-5875. PMCID PMC7667864. doi:10.1021/acsmedchemlett.0c00340.

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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 pyrroloin-dolines 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.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Blom, Annet E. M.0000-0002-7441-4893
Su, Justin Y.0000-0002-1946-3908
Repka, Lindsay M.0000-0002-6250-0268
Reisman, Sarah E.0000-0001-8244-9300
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2020 American Chemical Society. Received 18 June 2020. Accepted 15 September 2020. Published online 21 September 2020. We thank Alex Maolanon and Katie Chan for early synthesis efforts, as well as Chris B. Marotta and Kristina Daeffler for performing the preliminary Cys-loop screen. We are grateful to Scott Virgil and the Caltech Center for Catalysis and Chemical Synthesis for access to analytical equipment and assistance with performing preparative chiral HPLC and SFC resolutions. S.E.R. is a Heritage Medical Research Institute Investigator. Financial support from the NIH (S.E.R. R35GM118191-01) is gratefully acknowledged. Author Contributions. All authors have given approval to the final version of the manuscript. The authors declare no competing financial interest.
Group:Heritage Medical Research Institute
Funding AgencyGrant Number
Subject Keywords:GABA_A receptor, Cys-loop, positive allosteric modulator, ion channel, pyrroloindoline
Issue or Number:11
PubMed Central ID:PMC7667864
Record Number:CaltechAUTHORS:20200924-152452617
Persistent URL:
Official Citation:Synthesis and Biological Evaluation of Pyrroloindolines as Positive Allosteric Modulators of the α1β2γ2 GABAA Receptor. Annet E. M. Blom, Justin Y. Su, Lindsay M. Repka, Sarah E. Reisman, and Dennis A. Dougherty. ACS Medicinal Chemistry Letters 2020 11 (11), 2204-2211; DOI: 10.1021/acsmedchemlett.0c00340
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105531
Deposited By: George Porter
Deposited On:24 Sep 2020 22:42
Last Modified:08 Feb 2022 23:43

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