Defense Date


Document Type


Degree Name

Doctor of Philosophy


Medicinal Chemistry

First Advisor

Richard Westkaemper


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.


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Date of Submission

August 2009