Structure-activity relationships for serotonin transporter and dopamine receptor selectivity

Agatonovic-Kustrin, Snezana, Davies, Paul and Turner, Joseph V. (2009) Structure-activity relationships for serotonin transporter and dopamine receptor selectivity. Medicinal Chemistry, 5 3: 271-278. doi:10.2174/157340609788185927


Author Agatonovic-Kustrin, Snezana
Davies, Paul
Turner, Joseph V.
Title Structure-activity relationships for serotonin transporter and dopamine receptor selectivity
Journal name Medicinal Chemistry   Check publisher's open access policy
ISSN 1573-4064
1875-6638
Publication date 2009-05
Sub-type Article (original research)
DOI 10.2174/157340609788185927
Volume 5
Issue 3
Start page 271
End page 278
Total pages 8
Place of publication Bussum, Netherlands
Publisher Bentham Science Publishers
Language eng
Formatted abstract
Antipsychotic medications have a diverse pharmacology with affinity for serotonergic, dopaminergic, adrenergic, histaminergic and cholinergic receptors. Their clinical use now also includes the treatment of mood disorders, thought to be mediated by serotonergic receptor activity. The aim of our study was to characterise the molecular properties of antipsychotic agents, and to develop a model that would indicate molecular specificity for the dopamine (D2) receptor and the serotonin (5-HT) transporter.

Back-propagation artificial neural networks (ANNs) were trained on a dataset of 47 ligands categorically assigned antidepressant or antipsychotic utility. The structure of each compound was encoded with 63 calculated molecular descriptors. ANN parameters including hidden neurons and input descriptors were optimised based on sensitivity analyses, with optimum models containing between four and 14 descriptors.

Predicted binding preferences were in excellent agreement with clinical antipsychotic or antidepressant utility. Validated models were further tested by use of an external prediction set of five drugs with unknown mechanism of action. The SAR models developed revealed the importance of simple molecular characteristics for differential binding to the D2 receptor and the 5-HT transporter. These included molecular size and shape, solubility parameters, hydrogen donating potential, electrostatic parameters, stereochemistry and presence of nitrogen.

The developed models and techniques employed are expected to be useful in the rational design of future therapeutic agents.
Keyword Theoretical descriptors
ANN
QSAR
SERT
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Thu, 03 Sep 2009, 08:11:25 EST by Mr Andrew Martlew on behalf of School of Medicine