Development of a negative allosteric modulator binding to the membrane surface of the β2AR

Language
en
Document Type
Doctoral Thesis
Issue Date
2022-09-12
Issue Year
2022
Authors
Omran, Anahid
Editor
Abstract

The previous collaborative efforts of our research group at FAU (under supervision of Prof. Peter Gmeiner), Prof. Brian Kobilka’s group (Stanford University), Prof. Brian Shoichet’s group (UCSF) and Prof. Roger Sunahara’s group (UCSD) have resulted in the discovery of AS408, a novel negative allosteric modulator (NAM) for the adrenergic beta-2 receptor (β2AR). The main aim of my project was to further improve the functional properties of AS408 by extending its structure-activity relationship (SAR) study. Despite the fact that AS408 is a small molecule, possesses few modifiable functional groups and binds to a simple binding pocket, we were able to thoroughly study each and every part of the ligand. Throughout the course of this SAR study, more than 40 structural analogues of AS408 were designed and synthesized by modifying its heterocyclic core and substituent. Alongside with the SAR studies, by establishing and developing a titration method to experimentally determine the pKa value of some interesting ligands, a meaningful relationship between the basicity and the NAM activity has been presented. Interestingly, this study led us to the discovery of very strong and potent NAMs and enabled us to identify the important structural features of the ligands, which are necessary for the activity.

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