A Novel Synthetic Approach To Increase Structural Diversity at the Aliphatic Tryptamine Nitrogen
- 01/09/2023
- 12:30 - 14:00
- Foyer 2nd floor
Abstract
| The 5-HT2A receptors have been implicated to play a key role in diseases such as schizophrenia, depression and anxiety disorders, which emphasizes their high therapeutic potential and makes them interesting targets for drug development. However, 5-HT2A receptors are closely related to 5-HT2B and 5-HT2C receptors with sequence identities of 41% and 46%, respectively, and it is therefore challenging to design and obtain selective 5-HT2A ligands (Kimura et al., 2019).It was recently shown that sterically demanding substituents at the aliphatic nitrogen of tryptamines improve the selectivity for the 5-HT2A receptor over the 5-HT2C receptor (Klein et al., 2021). Such compounds are difficult to obtain via the classical Speeter-Anthony tryptamine synthesis, which is limited to the coupling of a small scope of less sterically demanding amines. Furthermore, it is highly desirable to introduce groups with increased functionalization and diversity at the aliphatic tryptamine nitrogen than is possible with current strategies.
In order to address these shortcomings and further explore the structure-activity-relationships around the aliphatic tryptamine nitrogen, we established a novel synthetic route that allows the diversity-oriented synthesis of tryptamines with sterically demanding, diverse and functionalized substituents on the aliphatic nitrogen. The pharmacological properties of the first molecules obtained via this route will guide further structural optimizations for enhanced subtype selectivity. |
