Design and Synthesis of 5-Hydroxy-2-(3- phenylpropyl)chromones as Non-Nitrogenous Ligands for the Serotonin Receptor 2B

Abstract

Neurodegenerative diseases are a major health concern worldwide. Currently there are very few pharmacotherapies that can reverse or slow neurodegenerative disease progression. Accordingly, there are significant research efforts to identify molecules with unique mechanisms of action that can serve as neuroprotectants. The natural product 5- Hydroxy-2-(2-phenylethyl)chromone (5-HPEC, 9) has shown neuroprotective activity, but its mechanism of action is largely unknown. Studies from our labs identified 5-HPEC as a novel non-nitrogenous moderate affinity serotonin receptor 2B (5-HT2B) antagonist with a Ki = 2.5 μM. 5-HT2B antagonists have only recently been explored as neuroprotectants, thus efforts to improve the binding affinity of 5-HPEC at 5-HT2B were undertaken. Homologation of the C-2 alkyl chain in 5-HPEC to give 5-Hydroxy-2-(3- phenylpropyl)chromone (5-HPPC, 12) resulted in a 10 fold improvement in binding affinity (Ki = 0.25 μM) towards 5-HT2B. The work presented here are current efforts towards the rational design and synthesis of 5-HPPC derivatives to further explore the structure activity relationships for this class of compounds. Ligand docking studies of serotonin and 5-HPPC using the 5-HT2B crystal structure revealed a putative binding pocket consistent with previous site-directed mutagenesis data. Examination of the proposed binding pocket suggests the C-5 hydroxyl group is critical for high affinity due to hydrogen bonding with Ser139 and Asp135. Further evaluation of the binding pocket suggested binding affinity might be further improved by substitutions at the C-3' and C-4' positions of 5-HPPC. The synthetic route to access the desired C-3'/ C-4' derivatives involved a Heck Reaction, catalytic hydrogenation, Claisen condensation, and acid catalyzed cyclization. This approach was able to produce five 5-HPPC derivatives in 3- 57% yield over four steps. These derivatives are currently being evaluated for their affinity at 5-HT2B and the results will be used to help guide future derivative synthesis and in silico studies.