Synthesis and evaluation of arylpiperazine-reverse amides as biased dopamine D3 receptor ligands.
The dopamine D3 receptor (D3R) preferential ligands have been universally adopted as a strategy for the treatment of drug addiction and other neuropsychiatric disorders due to fewer side effects. However, the high sequence homology between D3R and the D2 receptor (D2R) challenges the development of D3R-biased compounds. Herein, we design and synthesize a novel series of reverse amide-piperazine hybrid ligands and evaluate their biological affinities in vitro. Compound 4d was found to be the most potent D3R-selective ligand among these hybrid derivatives. Molecular modeling revealed that extracellular loop 1 (EL1) and loop 2 (EL2) of D3R together likely contribute to D3R selectivity over D2R. In particular, Gly94 in EL1 of D3R may act as a molecular determinant for D3R specificity.
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
Yongkai
Y
Cao
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
Suresh
S
Paudel
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
Xiaowei
X
Zhang
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: kmkim@jnu.ac.kr.
Kyeong-Man
KM
Kim
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: shcheon@jnu.ac.kr.
Seung Hoon
SH
Cheon
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D050637:Receptors, Dopamine D3 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000577:Amides; D008024:Ligands; D010879:Piperazines; D050637:Receptors, Dopamine D3; D000077489:Piperazine
Dopamine D3 receptor; Molecular modeling; Reverse amide; Selectivity; Structure–activity relationships