Abstract
In this pilot study, a series of new 3,4-dihydroquinolin-2(1H)-one derivatives as potential dopamine receptor D2 (D2R) modulators were synthesized and evaluated in vitro. The preliminary structure–activity relationship disclosed that compound 5e exhibited the highest D2R affinity among the newly synthesized compounds. In addition, 5e showed a very low cytotoxic profile and a high probability to cross the blood–brain barrier, which is important considering the observed affinity. However, molecular modelling simulation revealed completely different binding mode of 5e compared to USC-D301, which might be the culprit of the reduced affinity of 5e toward D2R in comparison with USC-D301.
Highlights
Dopamine primarily mediates its effect through activation of dopamine receptors (DRs) [1]
Aripiprazole combines 3,4-dihydro-7hydroxyquinolin-2(1H)-one fragment attached at position 7- to 2,3-dichlorophenyl piperazine and is a member of large group of antipsychotics, so called 1,4-disubstituted arylpiperazines
The biological activity of this subgroup of compounds is encoded by an aromatic warhead, which controls intrinsic activity, and an amine moiety, which is responsible for the formation of a hydrogen bond to the crucial residue Asp3.32 in the transmembrane helix 3 of D2 type receptors (D2 Rs) [62]
Summary
Dopamine primarily mediates its effect through activation of dopamine receptors (DRs) [1]. There are a total of five DR subtypes that are members of the G-protein-coupled receptors (GPCRs) [2], and are further divided into two classes according to the structure. The D1 -like family includes D1 Rs and D5 Rs, whereas D2–4 Rs belong to the D2 -like family [1,2,3]. The main difference between both families is that D1 -like family activate adenylate cyclase (AC), which leads to production of cyclic adenosine monophosphate (cAMP), whereas D2 -like stimulates AC activity. Dopamine D2 type receptors (D2 Rs) are integral membrane receptors coupled to G proteins with three extracellular loops, seven transmembrane domains, and three intracellular loops [4,5].
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