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

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.