“DESIGN AND SYNTHESIS OF MOLECULAR PROBES FOR THE STUDY OF 5-HT2A AND H1 RECEPTORS”
The serotonin (5-HT) receptors, with seven subtypes and at least fifteen distinct members, mediate a wide range of physiological functions both in the central nervous system and in the periphery. All members of the 5-HT family except the 5-HT3 subtype belong to the family of aminergic G protein-coup...
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ndltd-vcu.edu-oai-scholarscompass.vcu.edu-etd-28682017-03-17T08:32:14Z “DESIGN AND SYNTHESIS OF MOLECULAR PROBES FOR THE STUDY OF 5-HT2A AND H1 RECEPTORS” shah, Jitesh The serotonin (5-HT) receptors, with seven subtypes and at least fifteen distinct members, mediate a wide range of physiological functions both in the central nervous system and in the periphery. All members of the 5-HT family except the 5-HT3 subtype belong to the family of aminergic G protein-coupled receptors (GPCRs). Over the years, various molecules have been reported which act selectively at 5-HT2 receptors. However, there are no ligands that exhibit complete selectivity for one subpopulation of 5-HT2 receptors. Insight into how drugs bind to 5-HT2 receptors could contribute significantly to the development of subtype-selective agents with enhanced therapeutic effects. We have begun to address this challenge by the combined approach of chemical synthesis and molecular modeling. 9-(Aminomethyl)-9,10-dihydroanthracene (AMDA) a novel, selective 5-HT2 antagonist that also has modest affinity for the histamine (H1) receptor has been reported by Westkaemper et al. A structure-affinity relationships (SAFIR) study of AMDA and its analogs was carried out by studying the effects of N-alkylation, variation of the amine-ring system linker chain length and constraint of the aromatic rings on the binding affinities of the compounds for the 5-HT2A and H1 receptors. The results of the docking studies carried out on the homology models of 5-HT2A and H1 receptors were consistent with the observed binding affinity data for both receptors. In order to explore the additional binding site interactions of 5-HT2A receptor, synthesis and testing of the ring-annulated analogs of AMDA were carried out. A 3-methoxytetraphen analog of AMDA (26) showed high affinity (Ki = 21 nM) and selectivity (126-fold) for 5-HT2A receptor as compared to H1 receptor (Ki = 2640 nM). Further, to test the utility of our homology models, and investigate the binding site specific interaction, a compound was synthesized and tested that lacks a basic amine and contains an acidic functionality designed specifically to interact with lysine K1915.39 found in H1 but not in 5-HT2A receptor. This compound would thus be both H1-selective and demonstrate that a basic amine-D3.32 interaction is not necessary for high affinity. The synthesized compound (34) lacking the nitrogen atom showed moderate affinity at the H1 receptor (Ki = 250 nM), and lacked affinity for 5-HT2A receptors. The modeled ligand orientations in combination with the observed affinity data provide another example of a successful structure-based design strategy. 2009-05-26T07:00:00Z text application/pdf http://scholarscompass.vcu.edu/etd/1869 http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=2868&context=etd © The Author Theses and Dissertations VCU Scholars Compass Chemicals and Drugs Medicine and Health Sciences |
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Chemicals and Drugs Medicine and Health Sciences shah, Jitesh “DESIGN AND SYNTHESIS OF MOLECULAR PROBES FOR THE STUDY OF 5-HT2A AND H1 RECEPTORS” |
description |
The serotonin (5-HT) receptors, with seven subtypes and at least fifteen distinct members, mediate a wide range of physiological functions both in the central nervous system and in the periphery. All members of the 5-HT family except the 5-HT3 subtype belong to the family of aminergic G protein-coupled receptors (GPCRs). Over the years, various molecules have been reported which act selectively at 5-HT2 receptors. However, there are no ligands that exhibit complete selectivity for one subpopulation of 5-HT2 receptors. Insight into how drugs bind to 5-HT2 receptors could contribute significantly to the development of subtype-selective agents with enhanced therapeutic effects. We have begun to address this challenge by the combined approach of chemical synthesis and molecular modeling. 9-(Aminomethyl)-9,10-dihydroanthracene (AMDA) a novel, selective 5-HT2 antagonist that also has modest affinity for the histamine (H1) receptor has been reported by Westkaemper et al. A structure-affinity relationships (SAFIR) study of AMDA and its analogs was carried out by studying the effects of N-alkylation, variation of the amine-ring system linker chain length and constraint of the aromatic rings on the binding affinities of the compounds for the 5-HT2A and H1 receptors. The results of the docking studies carried out on the homology models of 5-HT2A and H1 receptors were consistent with the observed binding affinity data for both receptors. In order to explore the additional binding site interactions of 5-HT2A receptor, synthesis and testing of the ring-annulated analogs of AMDA were carried out. A 3-methoxytetraphen analog of AMDA (26) showed high affinity (Ki = 21 nM) and selectivity (126-fold) for 5-HT2A receptor as compared to H1 receptor (Ki = 2640 nM). Further, to test the utility of our homology models, and investigate the binding site specific interaction, a compound was synthesized and tested that lacks a basic amine and contains an acidic functionality designed specifically to interact with lysine K1915.39 found in H1 but not in 5-HT2A receptor. This compound would thus be both H1-selective and demonstrate that a basic amine-D3.32 interaction is not necessary for high affinity. The synthesized compound (34) lacking the nitrogen atom showed moderate affinity at the H1 receptor (Ki = 250 nM), and lacked affinity for 5-HT2A receptors. The modeled ligand orientations in combination with the observed affinity data provide another example of a successful structure-based design strategy. |
author |
shah, Jitesh |
author_facet |
shah, Jitesh |
author_sort |
shah, Jitesh |
title |
“DESIGN AND SYNTHESIS OF MOLECULAR PROBES FOR THE STUDY OF 5-HT2A AND H1 RECEPTORS” |
title_short |
“DESIGN AND SYNTHESIS OF MOLECULAR PROBES FOR THE STUDY OF 5-HT2A AND H1 RECEPTORS” |
title_full |
“DESIGN AND SYNTHESIS OF MOLECULAR PROBES FOR THE STUDY OF 5-HT2A AND H1 RECEPTORS” |
title_fullStr |
“DESIGN AND SYNTHESIS OF MOLECULAR PROBES FOR THE STUDY OF 5-HT2A AND H1 RECEPTORS” |
title_full_unstemmed |
“DESIGN AND SYNTHESIS OF MOLECULAR PROBES FOR THE STUDY OF 5-HT2A AND H1 RECEPTORS” |
title_sort |
“design and synthesis of molecular probes for the study of 5-ht2a and h1 receptors” |
publisher |
VCU Scholars Compass |
publishDate |
2009 |
url |
http://scholarscompass.vcu.edu/etd/1869 http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=2868&context=etd |
work_keys_str_mv |
AT shahjitesh designandsynthesisofmolecularprobesforthestudyof5ht2aandh1receptors |
_version_ |
1718428940734824448 |