Metabotropic glutamate receptor 5 (mGluR5) has been identified as a central entity in the etiology of several neurological and neurodegenerative disorders, e. g. schizophrenia, Parkinson's disease, autism, and fragile X-syndrome. The development of a synthetic pathway to a rigid molecular scaffold is presented. This scaffold has a balance of physicochemical properties required to penetrate the central nervous system and carries functionalities that are known to interact with the allosteric binding sites of this glutamate receptor. The pathway builds on structural features of the alkaloid ibogaine, a psychoactive compound found in e. g. Voacanga africana, a tree native to Western Africa. The strategy is to integrate functional groups and building blocks that are known to bind to the allosteric binding sites of mGluR5 into the cage-like structure of ibogaine. Through the N-alkylation of substituted pyridines with alkenyl building blocks pyridinium salts are formed. These are converted to dihydropyridines through reaction with Grignard reagents. Experiments are under way to complete the synthesis of the scaffold through an intramolecular Dies-Alder reaction. The hydrophilicity and bulkiness of the products, the number of sites capable of forming hydrogen bonds and the spacial orientation of functionalities can be adjusted during a hit-to-lead approach of drug development.

Synthetic pathway to a modulator of mGluR5

254th National Meeting (2017)

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