@phdthesis{Geyer2023,
  author    = {Geyer, Florian},
  title     = {Targeting of M\(_2\) and M\(_4\) Muscarinic Receptor Subtypes with New Dualsteric Ligands},
  doi       = {10.25972/OPUS-27150},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271506},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {As part of the parasympathetic nervous system, muscarinic receptors are involved in the regulation of numerous functions in the human body. However, targeting a specific subtype of muscarinic receptors is challenging due to the high degree of similarity within the binding site of the endogenous neurotransmitter acetylcholine. Therefore, this study focused on the investigation of dualsteric ligands. Such hybrid ligands target the orthosteric acetylcholine binding site and, simultaneously, a distinct allosteric binding site. Since allosteric binding regions show significant structural differences throughout muscarinic receptor subtypes, it was aimed to produce selective ligands by means of combination of two pharmacophores in one molecule. Herein, the thienopyridine derivatives LY2033298 and LY2119620 were chosen as allosteric moieties. Based on literature studies, the investigated allosteric modulators were analyzed in terms of adequate attachment points for the combination with an orthosteric agonist. As orthosteric units, muscarinic superagonist iperoxo, xanomeline, and TMA were applied in this work. Since the distance between orthosteric and allosteric moieties plays a crucial role for dualsteric ligand binding, the linker chain length was also varied. Pharmacological investigations of the synthesized hybrid ligands were perfomed via FRET- and BRET-assay measurements.},
  subject      = {GTP-bindende Proteine},
  language  = {en}
}