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.

2-苯基环丙基甲胺（2-Phenylcyclopropylmethylamine，PCPMA）类似物此前已有报道作为选择性5-羟色胺2C受体激动剂。基于该相同骨架，本研究设计并合成了一系列双位点衍生物作为多巴胺D3受体（D3R）配体。其中多款新型化合物对D3R展现出高结合亲和力与优异的选择性。化合物(1R,2R)-22e及其对映异构体(1S,2S)-22e对D3R的结合亲和力相当，但前者为强效D3R激动剂，后者则发挥拮抗剂作用。分子对接研究显示，PCPMA骨架在D3R正构结合口袋内呈现不同的结合构象，这或可解释该对对映异构体的功能特性差异。化合物(1R,2R)-30q对D3R展现出高结合亲和力（抑制常数Ki=2.2 nM），同时具备良好的选择性，且在小鼠体内表现出优异的生物利用度与血脑屏障穿透能力。上述研究结果表明，PCPMA骨架可作为胺能G蛋白偶联受体（GPCR）配体设计的优势骨架。