Object

Title: Novel functionally selective agonists of the serotonin 5 HT1A receptor

Abstract:

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.

Place of publishing:

Kraków

Level of degree:

2 - studia doktoranckie

Degree discipline:

farmacja

Degree grantor:

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

Promoter:

Marcin Kołaczkowski ; Adam Bucki

Date issued:

2018

Identifier:

oai:dl.cm-uj.krakow.pl:4278

Call number:

ZB-128497

ControlNumberVIRTUA:

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Access rights:

nieograniczony

Location of original object:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum

Object collections:

Last modified:

May 24, 2021

In our library since:

May 6, 2019

Number of object content hits:

34

All available object's versions:

http://dl.cm-uj.krakow.pl:8080/publication/4279

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ZB-128497 May 24, 2021
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