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Title: Synthesis of new 2-substituted propionic acid derivatives - GABA and/or monoamines reuptake inhibitors
Abstract:
The solute carrier (SLC) group of membrane transport proteins are promising targets for treatment and studies of central nervous system (CNS) pathophysiology. Dysfunctions in CNS are related with deviation from homeostatic level of biogenic monoamines and gamma-aminobutyric acid (GABA) concentrations. Such deviation are postuled as a neurological basis for several illnesses such as epilepsy, schizophrenia, insomnia, neuropathic pain or Parkinson disease. Firsts part of disertation briefly descripe biological basis and mechanism of monoamines and GABA reuptake as well as pharmaceutical acting along the same pathway. Among GABA reuptake inhibitors only tiagabine, a selective mGAT1 inhibitor, used for treatment of epilepsy. Discovery of novel inhibitors, which will have subtype selectivity for mGAT2-mGAT4, may help in understanding of the structure and biological functions of these particular proteins. Well-established strategies employed for design of small molecules acting on monoamine reuptake are focused on obtaining compounds that selectively block the action of dopamine transporter (DAT) or ones characterized by high affinity to dopamine transporter (DAT), noradrenaline transporter (NET) and serotonin transporter (SERT). Original results of research carried out by the author concern with those two targets. First, the work was directed towards obtaining small organic mole ; cules able to selectively inhibit a particular GAT protein. The second goal was to design and prepare molecules with simultaneous affinity toward DAT, NERT and SERT. In vitro biological evaluation of newly synthesized molecules was performed in cooperation with Ludwig Maximilian University of Munich. In vivo studies were conducted in the Department of Pharmacodynamics, Faculty of Pharmacy JUMC in Krakow. Propionic acid analogues have been used as a starting point in designing novel GABA uptake inhibitors.Within this thesis, an afficient synthetic procedure towards these compounds was developed. Cross examination of GABA and gamma-hydroxybutyric acid (GHB) derivatives allowed to identify important structural fragments which are possible pharmacophores responsible for the observed activity.As the results six series of serine derivatives along with derivatives of 2,3-diaminoproponic acid have been optained. The results of in vitro biological activity assays imply moderate inhibition of GABA uptake comparable to other known ligands, but what was gained is clear selectivity toward differnet isoforms of GAT proteins. In vivo examination utilizing a mouse model of neuropathic pain suggests that the obtained, novel compounds show antinociceptive properties. Efforts aimed at the discovery of novel DAT, SERT, NET inhibitors resulted in formulation of new amine building blocks ; . Additionally a new functional group was introduced, which enhanced affinity to DA, NE, 5-HT transporters. A set of seventeen compounds based on N-benzylamide analogues of GABA and GHB was obtained with reasonably high in vitro activity for NET, SERT and DAT. Among the factors affecting selectivity and activity, one can enlist the substituents in N-benzylamide aromatic ring. It should be also noted that simplification in ligand structure affects observed in vitro affinities. The results of recently conducted in vivo examinations, concerning analgesic properties, confirm potential activity of one of the obtained selective DAT inhibitors after systemic administration. To summarize, the obtained preliminary results are a good starting point for an advanced investigation toward selective DAT, NET and SERT inhibitors. In the course of conducted research, important structural factors present in the synthetized ligands were identified. Novel promising lead structures were proposed among N-benzylamide derivatives of 4-aminobutanoic acid or 4-hydroxybutanoic acid prove to be promising hits.
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Malawska, Barbara ; Kulig, Katarzyna
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Last modified:
Jan 24, 2024
In our library since:
May 5, 2022
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7
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http://dl.cm-uj.krakow.pl:8080/publication/4645
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| Edition name | Date |
|---|---|
| ZB-128009 | Jan 24, 2024 |
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