当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands.

Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands.

Abstract：

:2-Phenylcyclopropylmethylamine (PCPMA) analogues have been reported as selective serotonin 2C agonists. On the basis of the same scaffold, we designed and synthesized a series of bitopic derivatives as dopamine D3R ligands. A number of these new compounds show a high binding affinity for D3R with excellent selectivity. Compound (1R,2R)-22e and its enantiomer (1S,2S)-22e show a comparable binding affinity for the D3R, but the former is a potent D3R agonist, while the latter acts as an antagonist. Molecular docking studies revealed different binding poses of the PCPMA moiety within the orthosteric binding pocket of the D3R, which might explain the different functional profiles of the enantiomers. Compound (1R,2R)-30q shows a high binding affinity for the D3R (Ki = 2.2 nM) along with good selectivity, as well as good bioavailability and brain penetration properties in mice. These results reveal that the PCPMA scaffold may serve as a privileged scaffold for the design of aminergic GPCR ligands.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Tan L,Zhou Q,Yan W,Sun J,Kozikowski AP,Zhao S,Huang XP,Cheng J

doi

10.1021/acs.jmedchem.9b01835

subject

Has Abstract

pub_date

2020-05-14 00:00:00

pages

4579-4602

issue

9

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章

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