4.7 Article

Structure Activity Relationships for a Series of Eticlopride-Based Dopamine D2/D3 Receptor Bitopic Ligands

Journal

JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 20, Pages 15313-15333

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01353

Keywords

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Funding

  1. National Institute on Drug Abuse Intramural Research Program [ZIA DA000424, Z1A DA000609]

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The crystal structure of dopamine D-3 receptor in complex with eticlopride led to the design of bitopic ligands exploring various alterations to the pyrrolidine ring, which were found to impact binding affinities with dopamine D2R/D3R. The study showed that small pyrrolidine N-alkyl groups were poorly tolerated, and O-alkylated analogues exhibited higher affinities compared to N-alkylated ones. Molecular models suggested that modifications at the 4-position could be well-tolerated for future D2R/D3R bioconjugate tools.
The crystal structure of the dopamine D-3 receptor (D3R) in complex with eticlopride inspired the design of bitopic ligands that explored (1) N-alkylation of the eticlopride's pyrrolidine ring, (2) shifting of the position of the pyrrolidine nitrogen, (3) expansion of the pyrrolidine ring system, and (4) incorporation of O-alkylations at the 4-position. Structure activity relationships (SAR) revealed that moving the N- or expanding the pyrrolidine ring was detrimental to D2R/D3R binding affinities. Small pyrrolidine N-alkyl groups were poorly tolerated, but the addition of a linker and secondary pharmacophore (SP) improved affinities. Moreover, O-alkylated analogues showed higher binding affinities compared to analogously N-alkylated compounds, e.g., O-alkylated 33 (D3R, 0.436 nM and D2R, 1.77 nM) vs the N-alkylated 11 (D3R, 6.97 nM and D2R, 25.3 nM). All lead molecules were functional D2R/D3R antagonists. Molecular models confirmed that 4-position modifications would be well-tolerated for future D2R/D3R bioconjugate tools that require long linkers and or sterically bulky groups.

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