Synthesis, Docking, 3-D-Qsar, and Biological Assays of Novel Indole Derivatives Targeting Serotonin Transporter, Dopamine D2 Receptor, and Mao-A Enzyme: In the Pursuit for Potential Multitarget Directed Ligands (original) (raw)
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Synthesis, in silico, and in vitro studies of novel dopamine D 2 and D 3 receptor ligands
Archiv der Pharmazie, 2021
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]).
Synthesis, in silico, and in vitro studies of novel dopamine D2and D3receptor ligands
Archiv Der Pharmazie, 2021
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]).
European Journal of Medicinal Chemistry, 2005
Arylpiperazin-1-yl)propyl]-1H-benzimidazoles and 5-[2-(4-arylpiperazin-1-yl)ethoxy]-1H-benzimidazoles were synthesized and their affinity for the D 1 , D 2 and 5-HT 1A receptors examined. They expressed a rather high affinity for the D 2 dopamine receptor. The main features of ligand-D 2 receptor interactions revealed by docking analyses were: salt bridge between piperazine ring protonated N 1 and Asp 86, hydrogen bonds of ligand bezimidazole part with Ser 141, Ser 122 and His 189, edge-to-face interactions of arylpiperazine aromatic ring with Phe 178, Tyr 216 and Trp 182 and hydrogen bond between ethereal oxygen in ethylenoxy ligands and hydrogen of Phe 185 or Trp 115. The most active 5-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethoxy}-1,3-dihydro-2H-benzimidazole-2-thione (27) has a maximal number of attractive interactions. A satisfactory correlation between docking of the compounds into the D 2 receptor and competition binding results was observed.
Journal of Medicinal Chemistry, 2008
±)-Citalopram (1, 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5carbonitrile), and its eutomer, escitalopram (S(+)-1) are selective serotonin reuptake inhibitors (SSRIs) that are used clinically to treat anxiety and depression. To further explore structureactivity relationships at the serotonin transporter (SERT), a series of (±)-4-and 5-substituted citalopram analogues were designed, synthesized and evaluated for binding at the SERT, dopamine transporter (DAT) and norepinephrine transporter (NET) in native rodent tissue. Many of these analogues showed high SERT binding affinities (K i = 1-40 nM) and selectivities over both NET and DAT. Selected enantiomeric pairs of analogues were synthesized and both retained enantioselectivity as with S-and R-1, wherein S > R at the SERT. In addition, the enantiomeric pairs of 1 and 5 were tested for binding at the homologous bacterial Leucine transporter (LeuT), wherein low affinities and the absence of enantioselectivity suggested distinctive binding sites for these compounds at SERT as compared to LeuT. These novel ligands will provide molecular tools to elucidate drug-protein interactions at the SERT and to relate those to behavioral actions, in vivo.
Tetrahedron, 1998
The rational design, synthesis, and evaluation of two novel series of 2-(aminomethyl)-3,4,7,9tetrahydro-2H-pyrano[2,3-e]indole and indolone derivatives are disclosed, based on the recently discovered I)2 agonist phenolic template prototype [i.e. the 7-OH-2-(aminomethyl)chroman nucleus]. The indolones were observed to have higher affinity and intrinsic activity than the corresponding indoles. © 1998 Elsevier Science Ltd. All rights reserved.
Recent advances in the search for D3- and D4-selective drugs: probes, models and candidates
Trends in Pharmacological Sciences, 2011
Dopamine D 2 -like receptors (including D 2 , D 3 and D 4 ) belong to the 'rhodopsin-like' family of G protein-coupled receptors (GPCRs), which represent the largest group of targets for bioactive molecules. Due to their high sequence similarity, the design of subtype-selective ligands requires rational and effective strategies. The general formula of 1,4-disubstituted aromatic piperidines and piperazines (1,4-DAPs) was extracted from classical dopaminergic drugs. The biological properties of this compound family are encoded by an aromatic head group that controls intrinsic activity, an amine moiety and a lipophilic appendage. D 3 -and D 4 -selective molecular probes and drug candidates were generated from the general formula of 1,4-DAP. Formal structural rearrangement led to investigational drugs beyond the 1,4-DAP structure. The very recent publication of the Xray crystal structure of D 3 should facilitate efficient discovery of unprecedented chemotypes. However, the development of D 3 -selective agonists, functionally selective ligands and the exploitation of homo-and heteromers remain challenging.
Functionally Selective Dopamine D 2 /D 3 Receptor Agonists Comprising an Enyne Moiety
Journal of Medicinal Chemistry, 2013
Contents 1) 1 Hand 13 C-NMR Data of the Target Compounds……………………………. S2 2) HPLC Data of the Target Compounds…………………………………………. S8 3) Chiral Separation………………………………………………………………… S14 4) X-ray Crystal Structure Determination of 3,5-dinitrobenzamide (S)-7………. S15 5) Dose-Response Curves of the Target Compounds in the [ 35 S]GTPγS Assay… S26 6) Representative Dose-Response Curves of the Reference Compounds Ropinirole and Rotigotine in a [ 35 S]GTPγS Assay with D 2long Expressing Cells………………..… S29 7) Comparison of the Binding Affinities of Representative Compounds at the D 2long Receptor Stably Expressed in CHO Cells and Transiently Expressed in HEK 293 Cells as well as at Membranes from Porcine Striatum………………………………….. S30 8) Amino acid sequence alignment of DRD2, DRD3, 5HT1B and 5HT2B………. S31 S2 1) 1 Hand 13 C-NMR Data and HPLC Data of the Target Compounds (R)-N-{4-[(4-Ethynylcyclohex-3-enyl)propylamino]butyl}biphenyl-4-carboxamide ((R)-1) 1 H-NMR 1 H (600MHz, CD 3 OD) 13 C-NMR 13 C (360MHz, CD 3 OD) S3 (R)-N-{4-[(4-Ethynylcyclohex-3-enyl)propylamino]butyl}pyrazolo[1,5-a]pyridine-2carboxamide ((R)-2a). 1 H-NMR 1 H (600MHz, CDCl 3) 13 C-NMR 13 C (360MHz, CDCl 3) S4 (R)-N-{4-[(4-Ethynylcyclohex-3-enyl)propylamino]butyl}pyrazolo[1,5-a]pyridine-3carboxamide ((R)-2b) 1 H-NMR 1 H (360MHz, CDCl 3) 13 C-NMR 13 C (600MHz, CDCl 3) S5 (R)-4-[3-(1-Butyl-1H-1,2,3-triazol-4-yl)propoxy]-N-{4-[(6-ethynylcyclohex-3enyl)propylamino]-butyl}-3-methoxybenzamide ((R)-2c) 1 H-NMR 1 H (360MHz, CDCl 3) 13 C-NMR 13 C (360MHz, CDCl 3) S6 (R)-N-{4-[(4-Ethynylcyclohex-3-enyl)propylamino]butyl}benzo[b]thiophene-2carboxamide ((R)-2d). 1 H-NMR 1 H (600MHz, CDCl 3) 13 C-NMR 13 C (360MHz, CDCl 3)
ACS Omega
The search for synthetic selective compounds for G-protein-coupled receptors has provided a myriad of molecules with high selectivity and therapeutic potential. In some cases, however, selectivity is difficult to obtain. For instance, the selectivity ratio is relatively low for compounds acting on D 2 and D 3 dopamine receptors, which are targets of neurodegenerative diseases such as Parkinson's and Huntington's. From a therapeutic point of view, it is of interest the relative recent discovery of biased agonism, which is characterized by different signaling pathways engaged by different compounds acting on a given receptor. The aim of this paper was to investigate whether new piribedil-derived compounds could display higher selectivity for D 2 or D 3 receptor and/or provide biased signaling. The results show that selectivity was not different, but that one of the molecules described here, 5-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)quinolin-8-ol (10), does engage Gi-mediated signaling via D 2 or D 3 receptors, whereas it does not activate the mitogen-activated-protein kinase pathway, which is usually activated by dopamine receptor agonists.