posted on 2021-10-12, 13:05authored byAnver
Basha Shaik, Comfort A. Boateng, Francisco O. Battiti, Alessandro Bonifazi, Jianjing Cao, Li Chen, Rezvan Chitsazi, Saiprasad Ravi, Kuo Hao Lee, Lei Shi, Amy Hauck Newman
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 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.