Tytuł:

Novel functionally selective agonists of the serotonin 5 HT1A receptor

Autor:

Śniecikowska, Joanna

Temat i słowa kluczowe:

functional selectivity ; biased agonism ; 5-HT1A receptor agonist ; serotonin ; 5-HT1A receptor

Abstrakt:

The subject of the doctoral dissertation was the discovery of a new generation of functionally selective 5-HT1A serotonin receptor agonists, of significant importance in the search for the therapy of psychiatric and neurodegenerative disorders. Designed with the support of molecular modeling, a library of 65 new 1- (1-benzoylpiperidin-4-yl) methanamine derivatives was synthesized by chemical synthesis, of which as many as 48 had subnanomolar affinity, and one of the compounds was characterized by the highest affinity of all the 5 HT1AR ligands described so far (Ki = 0.00016 nM). Seventeen new 5-HT1A receptor agonists with different functional activity profiles were identified, including compounds strongly favoring ERK1 / 2 phosphorylation or β-arrestin recruitment, with very high bias factors (> 1000x). The new series was characterized by high selectivity for the adrenergic α1 and dopaminergic D2 receptors as well as high values of parameters predicting the drug-like and developability properties of the tested compounds (CNS MPO, Fsp3 or LELP).For the lead structure, high selectivity against 44 off-targets, high metabolic stability and favorable ADME parameters have been demonstrated. In rat studies it showed striking and dose-dependent antidepressant activity, observed from very low doses after oral administration (MED = 0.16 mg/kg), achieving an exceptionally high effect size (total reduction of immobility in the Porsolt test).All the obtained compounds are the subject of international patent application WO2017220799.

Miejsce wydania:

Kraków

Stopień studiów:

2 - studia doktoranckie

Dyscyplina:

farmacja

Instytucja nadająca tytuł:

Jagiellonian University. Medical College. Faculty of Pharmacy. Chair of Pharmaceutical Chemistry. Department of Medicinal Chemistry.

Promotor:

Marcin Kołaczkowski ; Adam Bucki

Data:

2018

Data wydania:

2018

Typ:

Praca doktorska

Sygnatura:

ZB-128497

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Prawa dostępu:

nieograniczony

Lokalizacja oryginału:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum