Dysfunction of dopaminergic receptor signaling in the brain is a hallmark of a number of neurodegenerative pathologies. Of the five dopamine receptors, the D3 subtype has emerged as a promising target for treating neurodegenerative diseases, especially Parkinson’s disease, due to the specific distribution of this receptor in limbic and nigrostriatal brain regions known to be associated with motor functions. Not only have D3-selective agonists shown positive effects in re-establishing control of motor activity in animals, but they also display neuroprotective activity and may be important in reducing the dyskinesia side-effect often seen with current non-selective dopaminergic therapies. Herein we report the extension of our previous studies of racemic 3-hydroxyphenyl pyrrolidines to their chiral analogues. We have used our best racemic D3 ligand, N-nonyl-3-hydroxyphenyl pyrrolidine 1 (Ki = 13 nM), as starting point. Synthesis, characterization and D3 receptor affinity of both the R- and S-enantiomer of 1 will be reported. In addition, we will describe SAR studies of new chiral N-functionalized-3-hydroxyphenylpyrrolidines (based upon the steric requirements of compound 1) in which the N-substituent has been designed to engage key residues in the secondary binding site of the D3 receptor to enhance affinity and selectivity.

Synthesis of N-functionalized chiral 3-hydroxyphenylpyrrolidines and their evaluation as selective D3 receptor ligands

253rd National Meeting (2017)

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