Title:

Structural modifications of arylpiperazine and arylsulfonamide serotonin 5-HT1A and 5-HT7 receptor ligands in search of factors determining selectivity

Author:

Bugno, Ryszard

Subject:

5-HT7 ; 5-HT1A ; receptors ; serotonin ; ligands

Abstract:

The PhD thesis focuses on structural factors determining selectivity of arylpiperazine and arylsulfonamide derivatives for 5-HTlA and 5-HT7 receptors. The synthesis and SAR analysis of pyrrolidine and benzotriazole derivatives confirmed that linearly extended conformation of LCAP is bioactive for 5-HTlA receptors, whereas this geometry is unfavorable for the 5-HT7 receptors. In the group of benzisoxazolepiperazine derivatives the use of sulfonamide fragment, additionally rigidified by the piperidine ring, is significant for high affinity for 5-HT7R; however, the activity toward 5-HT1AR (and others monoaminergic receptors) is not completely eliminated. It was found, that the lack of aromatic groups m the vicinity of protonated nitrogen atom (perhydroisoquinoline derivatives) is essential for selectivity to 5-HT7R vs 5-HT1AR. Docking studies showed that these ligands are located between helices 3, 6 and 7, within the so-called selective part of 5-HT7R binding pocket. Moreover, based on new arylsulfonamide derivatives the 3D QSAR pharmacophore model was generated. It extends the previous selectivity hypothesis (obtained in structure-based approach), by defining the additional hydrophobic region, located near aromatic feature.

Place of publishing:

Kraków

Level of degree:

2 - studia doktoranckie

Degree discipline:

farmakologia

Degree grantor:

Wydział Farmaceutyczny

Promoter:

Bojarski, Andrzej J.

Date:

2010

Date issued:

2009

Type:

Praca doktorska

Call number:

ZB-111670

Language:

pol

Access rights:

nieograniczony