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 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.
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.Attached Files
Accepted Version - ml0c00340.pdf
Supplemental Material - ml0c00340_si_001.pdf
Files
Name | Size | Download all |
---|---|---|
md5:b04b2c658ed4846369bd64f83496fec5
|
11.5 MB | Preview Download |
md5:640837c4a07388be5009364155c0a1b9
|
2.7 MB | Preview Download |
Additional details
- PMCID
- PMC7667864
- Eprint ID
- 105531
- Resolver ID
- CaltechAUTHORS:20200924-152452617
- NIH
- R35GM118191-01
- Created
-
2020-09-24Created from EPrint's datestamp field
- Updated
-
2023-07-17Created from EPrint's last_modified field
- Caltech groups
- Heritage Medical Research Institute