The dopamine D3 receptor has emerged as a potential novel target for the pharmaceutical treatment of several neurodegenerative and neuropsychiatric disorders such as Parkinson’s disease, schizophrenia, and drug dependence. With regard to Parkinson’s disease, great interest in the development of D3 selective agents was stimulated by the 1997 finding that L-DOPA treatment increases the expression of this receptor subtype in the basal ganglia. Thus, a D3 selective drug may provide a means to both enhance motor function while minimizing dyskinetic side-effects associated with L-DOPA therapy. Interestingly, a number of D2-subtype selective 3-hydroxyphenyl-substitued piperidine (e.g. 3-PPP) and pyrrolidine analogues were evaluated and examined in vivo and vitro before cloning of the D3 receptor. For some of these compounds, more recent studies have shown that they indeed possess varying activity and selective for the D3 receptor. Herein we report the synthesis, characterization and full dopamine (D1-D5) receptor binding data for series of new N-substituted-3-hydroxyphenylpyrrolidines with comparisons to previously reported analogues. Our SAR strategy has been to keep the 3-hydroxyphenylpyrrolidine motif constant while varying the pyrrolidine N-substituent in order to probe the secondary binding site of the D3 receptor with the overall goals of increasing potency and selectivity. Several new analogues with extended lipophilic N-substitution have shown excellent D3 potency.

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

251st National Meeting (2016)

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