Because
of the large degree of homology among dopamine D2-like
receptors, discovering ligands capable of discriminating between
the D2, D3, and D4 receptor subtypes
remains a significant challenge. Previous work has exemplified the
use of bitopic ligands as a powerful strategy in achieving subtype
selectivity for agonists and antagonists alike. Inspired by the potential
for chemical modification of the D3 preferential agonists
(+)-PD128,907 (1) and PF592,379 (2), we
synthesized bitopic structures to further improve their D3R selectivity. We found that the (2S,5S) conformation of scaffold 2 resulted in a privileged
architecture with increased affinity and selectivity for the D3R. In addition, a cyclopropyl moiety incorporated into the
linker and full resolution of the chiral centers resulted in lead
compound 53 and eutomer 53a that demonstrate
significantly higher D3R binding selectivities than the
reference compounds. Moreover, the favorable metabolic stability in
rat liver microsomes supports future studies in in vivo models of
dopamine system dysregulation.
Dopamine D 3 receptors (D 3 R) play a critical role in neuropsychiatric conditions including substance use disorders (SUD). Recently, we reported a series of N-(3-hydroxy-4-(4-phenylpiperazin-1yl)butyl)-1H-indole-2-carboxamide analogues as high affinity and selective D 3 R lead molecules for the treatment of opioid use disorders (OUD). Further optimization led to a series of analogues that replaced the 3-OH with a 3-F in the linker between the primary pharmacophore (PP) and secondary pharmacophore (SP). Among the 3-F-compounds, 9b demonstrated the highest D 3 R binding affinity (K i = 0.756 nM) and was 327-fold selective for D 3 R over D 2 R. In addition, modification of the PP or SP with a 3,4-(methylenedioxy)phenyl group was also examined. Further, an enantioselective synthesis as well as chiral HPLC methods were developed to give enantiopure R-and S-enantiomers of the four lead compounds. Off-target binding affinities, functional efficacies, and metabolic profiles revealed critical structural components for D 3 R selectivity as well as drug-like features required for development as pharmacotherapeutics.
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