Synthesis, in silico, and in vitro studies of novel dopamine D₂ and D₃ receptor ligands

Abstract

Dopamine is an important neurotransmitter in the human brain and its altered concentrations can lead to various neurological diseases. We studied the binding of novel compounds at the dopamine D 2 (D 2 R) and D 3 (D 3 R) receptor subtypes, which belong to the D 2 -like receptor family. The synthesis, in silico, and in vitro characterization of 10 dopamine receptor ligands were performed. Novel ligands were docked into the D 2 R and D 3 R crystal structures to examine the precise binding mode. A quantum mechanics/molecular mechanics study was performed to gain insights into the nature of the intermolecular interactions between the newly introduced pentafluorosulfanyl (SF 5 ) moiety and D 2 R and D 3 R. A radioligand displacement assay determined that all of the ligands showed moderate-to-low nanomolar affinities at D 2 R and D 3 R, with a slight preference for D 3 R, which was confirmed in the in silico studies. N-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-4-(pentafluoro-λ6-sulfanyl)benzamide (7i) showed the highest D 3 R affinity and selectivity (pK i values of 7.14 [D 2 R] and 8.42 [D 3 R]).

Recent advances in dopamine D2 receptor ligands in the treatment of neuropsychiatric disorders

“…The most common linkage between the primary and secondary pharmacophores was mediated via an aliphatic linker that is terminated by an ether 585,588,602,605,616,617,620,656,701,763,768,788 or a secondary amide 473,479,489,515,516,583,602,700,776,785,788,799 bond. The aliphatic ether was further modified by adding a double bond, 788 a triple bond, an aromatic, cyclohexyl ring or a cyclopropyl rings, 584,800 or switched to a cyclic ether, 483,793,801 thio‐ether, 488,670,672 an aliphatic linker without any heteroatom 599,600,670,672,802 or an aromatic amine 478 .…”

“…For the allosteric binding site, in addition to variously substituted benzamides 466–469,472,473,477,484,783,799 or 3,4‐dihydroquinolin2‐(1 H )‐one moiety, 800,804 also fragments such as 6,7,8,9‐tetrahydro‐4 H ‐pyrido[1,2‐ a ]pyrimidin‐4‐one, 805 xanthine core, 802 trazodone, 806 phthalimide, 482 imidazolidine‐2‐one, 807 talipexole 808 or 2‐aminomethylchromane 809 were used. Following the discovery of cariprazine containing urea group, various urea‐based derivatives such as aliphatic sulfonamides, amides, carbamates 527,590,594,595,700 or cyclic or aliphatic scaffolds were implicated as secondary pharmacophore 163,475,783 …”

Recent Advances in the Synthesis and Medicinal Chemistry of SF5 and SF4Cl Compounds

“…The synthesis, in silico, and in vitro studies of novel SF5analogues of BP897, a potent D3R ligand (Ki =0.92nM), were reported by Stark at al. 55 (Figure 5). The synthesis of the target compounds was performed as shown in Scheme 62.…”

“…Scheme 62 Synthesis and affinity of dopamine D2 and D3 receptor SF5-ligands 55 The synthesis of a benzodiazepine Diazepam analogue bearing an SF5 group as a bioisosteric replacement of the chlorine atom was reported by Spencer et al 56 Acylation of commercially available 2-amino-5-SF5-benzophenone with chloroacetyl chloride followed by amination with hexamethylenetetramine, led to 7-SF5-5-phenyl-1H-benzo [1,4]diazepin-2(3H)-one, which was then converted into the desired compound by N-methylation (Scheme 63). Biological tests demonstrated that the substitution of Cl with the SF5 group led to a loss of potency (60-fold lower) in terms of potentiating GABAA receptor activation, probably due to a loss of ligand interaction with His102 in the GABAA receptor a subunit.…”

“…The synthesis, in silico, and in vitro studies of novel SF 5 -substituted analogues of BP897, a potent D 3 R ligand (K i =0.92 nM), were reported by Stark at al. 55 (Figure 5 ).…”