Depression and anxiety are serious conditions affecting 1 out of 20 Americans 12 years of age and older. While anxiety and depression are considered to be separate medical conditions, there are common clinical symptoms and neurological aspects which suggest a therapeutic agent with overlapping activity would be valuable. To this end significant research efforts have targeted two serotonin receptors 5-hydroxytryptamine -1A (HTR1A) and 5-hydroxytryptamine -2 (HTR2A). Adatanserin 1 was reported to have dual potent 5-HTR1A partial agonist and 5-HTR2 antagonist activity resulting in potent anxiolytic activity in preclinical models of anxiety and depression. As part of our undergraduate research program, we became interested in modification of adatanserin with a strategy of converting the amide group into a thioamide and subsequent alkylation. Thioamides have a more nucleophilic sulfur moiety which might affect the interaction with the receptors of interest. Despite the studies on many adatanserin analogues, thioadatanserin 2 has not been reported in the literature. We describe the preparation of 2 by direct thionation of 1 and its alkylation which resulted in unexpected products alkylated at the piperazine ring. Single crystal X-ray crystallography was used to determine the structure of bis benzylated product which was found to be 1-(2-((E-((3r, 5r, 7r)-adamantan-1-yl)benzylthio)methylene)amino)ethyl)-1-benzyl-4-(pyrimidin-2-yl)piperazin-1-ium bromide. The target compounds were evaluated for HTR1A agonist, HTR2A antagonist and HTR2C antagonist activities in the PathHunter® β-Arrestin assay using the Enzyme Fragment Complementation (EFC) with β-galactosidase as the functional reporter. In this assay, thioadatanserin exhibited potent agonist activity against the HTR1A with an EC50 value of 6.7 nM and moderate antagonist activity against the 2A receptor (HTR2A) with IC50 value of 62.3 nM and had no activity against the 2C receptor. Synthetic details and biology data will be disclosed in this poster.

Thioadatanserin and its derivatives: Potent dual 5- HTR1A agonists/5-HTR2A antagonists as potential depression and anxiety agents

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.