@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}
}
@article{HerzbergDornTrummetal.2022,
  author    = {Herzberg, Moriz and Dorn, Franziska and Trumm, Christoph and Kellert, Lars and Tiedt, Steffen and Feil, Katharina and K{\"u}pper, Clemens and Wollenweber, Frank and Liebig, Thomas and Zimmermann, Hanna},
  title     = {Middle cerebral artery M2 thrombectomy: safety and technical considerations in the German Stroke Registry (GSR)},
  series = {Journal of Clinical Medicine},
  volume    = {11},
  journal   = {Journal of Clinical Medicine},
  number    = {15},
  issn      = {2077-0383},
  doi       = {10.3390/jcm11154619},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286052},
  year      = {2022},
  abstract  = {There is ongoing debate concerning the safety and efficacy of various mechanical thrombectomy (MT) approaches for M2 occlusions. We compared these for MT in M2 versus M1 occlusions. Subgroup analyses of different technical approaches within the M2 MT cohort were also performed. Patients were included from the German Stroke Registry (GSR), a multicenter registry of consecutive MT patients. Primary outcomes were reperfusion success events. Secondary outcomes were early clinical improvement (improvement in NIHSS score > 4) and independent survival at 90 days (mRS 0-2). Out of 3804 patients, 2689 presented with M1 (71\%) and 1115 with isolated M2 occlusions (29\%). The mean age was 76 (CI 65-82) and 77 (CI 66-83) years, respectively. Except for baseline NIHSS (15 (CI 10-18) vs. 11 (CI 6-16), p < 0.001) and ASPECTS (9 (CI 7-10) vs. 9 (CI 8-10, p < 0.001), baseline demographics were balanced. Apart from a more frequent use of dedicated small vessel stent retrievers (svSR) in M2 (17.4\% vs. 3.0; p < 0.001), intraprocedural aspects were balanced. There was no difference in ICH at 24 h (11\%; p = 1.0), adverse events (14.4\% vs. 18.1\%; p = 0.63), clinical improvement (62.5\% vs. 61.4 \%; p = 0.57), mortality (26.9\% vs. 22.9\%; p = 0.23). In M2 MT, conventional stent retriever (cSR) achieved higher rates of mTICI3 (54.0\% vs. 37.7-42.0\%; p < 0.001), requiring more MT-maneuvers (7, CI 2-8) vs. 2 (CI 2-7)/(CI 2-2); p < 0.001) and without impact on efficacy and outcome. Real-life MT in M2 can be performed with equal safety and efficacy as in M1 occlusions. Different recanalization techniques including the use of svSR did not result in significant differences regarding safety, efficacy and outcome.},
  language  = {en}
}