Many neurological and psychiatric disorders like Parkinson’s disease, Fragile X syndrome, depression, schizophrenia and addiction have been linked to derailed signaling pathways associated with glutamate receptors, in particular with mGluR5. Due to the therapeutic benefits of targeting allosteric binding sites of this receptor, a synthetic pathway to a new mGluR5 allosteric modulator chemotype is being investigated. A synthetic pathway to a scaffold structurally related to the psychoactive natural product ibogaine is being investigated. It is the rapid distribution of ibogaine into the brain that makes this compound an interesting developmental starting point. Careful spatial arrangement of substituents known to interact strongly with the targeted receptor, a balance of physicochemical properties required to penetrate the CNS and metabolic innocuousness are considered in the design of the lead structure. The objective is to develop an orally available medication that fine-tunes the neuronal response to an overabundance of glutamate in synapses. Starting with simple pyridine derivatives, the scaffold is constructed by first synthesizing highly substituted dihydropyridines. These undergo intramolecular pericyclic reactions that produce a cage-like structure related to that of the neuroactive ibogaine. These cyclisations are highly stereocontrolled. Several precursors for the pericyclic reaction have been obtained and experiments to complete this last step of the synthetic pathway, the formation of a tricyclic system, are underway.

Biased allosteric modulators for mGluR5

251st National Meeting (2016)

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