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

ABSTRACT: The crystal structure of the dopamine D₃ 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 an

SUBMITTER: Shaik AB 

PROVIDER: S-EPMC9617622 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature