Discovery, Optimization, and Characterization of Novel D<sub>2</sub> Dopamine Receptor Selective Antagonists

Xiao, Jingbo; Free, R. Benjamin; Barnaeva, Elena; Conroy, Jennie; Doyle, Trevor; Miller, Brittney; Bryant-Genevier, Marthe; Taylor, Mercedes K.; Hu, Xin; Dulcey, Andrés E.; Southall, Noel; Ferrer, Marc; Titus, Steve; Zheng, Wei; Sibley, David R.; Marugán, Juan

doi:10.1021/jm500126s

Cited by 33 publications

(62 citation statements)

References 30 publications

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“…This work also indicated other top-ranked 3D QSAR hypotheses (AADRR.1398, AAPRR.3900, and ADHRR.2864) and two of them did not contain a positively charged group. This is in accordance with a few reports which have proven that the presence of a basic nitrogen atom enabling formation of the interaction of its protonated form and D3.32 is not indispensable for the dopamine D 2 receptor anchoring (Xiao et al 2014;Kaczor et al 2016b). Non-basic ligands are also known for some other aminergic GPCRs, e.g., the serotonin 5-HT 6 receptor (Ivachtchenko et al 2010) and for opioid receptors, including κ opioid receptor ligand, salvinorin A and μ opioid receptor ligands, carbonyl derivatives of 1-aryl-2-iminoimidazolidine (Matosiuk et al 2001(Matosiuk et al , 2002aSztanke et al 2005).…”

Section: Introductionsupporting

confidence: 93%

“…As it was already mentioned, Xiao et al (2014) obtained a series of the dopamine D 2 receptor antagonists without a protonatable nitrogen atom. Such ligands are worth detailed investigation as they may exhibit a unique pharmacological profile and may turn out better antipsychotics as well as may be developed as drugs with better pharmacokinetic properties.…”

Section: Introductionmentioning

confidence: 92%

“…For constructing 3D-QSAR models, the compounds should span at least four orders of activity magnitude and be well proportioned in each activity magnitude (Yuan et al 2014). The activity of the compounds was published elsewhere (Xiao et al 2014). The AC 50 (nM) values were converted into pAC 50 , which were applied as dependent variables for subsequent 3D-QSAR analyses.…”

Section: Comfa Studiesmentioning

confidence: 99%

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Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

et al. 2016

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The dopaminergic hypothesis of schizophrenia is the main concept explaining the direct reasons of schizophrenia and the effectiveness of current antipsychotics. All antipsychotics present on the market are potent dopamine D 2 receptor antagonists or partial agonists. In this work we investigate a series of dopamine D 2 receptor antagonists which do not fulfill the criteria of the classical pharmacophore model as they do not possess a protonatable nitrogen atom necessary to interact with the conserved Asp(3.32). Such compounds are interesting, inter alia, due to possible better pharmacokinetic profile when compared to basic, ionizable molecules. By means of homology modeling, molecular docking and molecular dynamics we determined that the compounds investigated interact with Asp(3.32) via their amide nitrogen atom. It was found that the studied compounds stabilize the receptor inactive conformation through the effect on the ionic lock, which is typical for GPCR antagonists. We constructed a CoMFA model for the studied compounds with the following statistics:63. The quality of the CoMFA model was confirmed by high value of R 2 of the test set, equal 0.96. The CoMFA model indicated two regions where bulky substituents are favored and two regions where bulky substituents are not beneficial. Two red contour regions near carbonyl groups were identified meaning that negative charge would be favored here. Furthermore, the S-oxide group is connected with blue contour region meaning that positive charge is favored in this position. These findings may be applied for further optimization of the studied compound series.

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Section: Introductionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 92%

Section: Comfa Studiesmentioning

confidence: 99%

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Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

et al. 2016

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“…[32] To verify the proposed binding mode of compound 2,w et ested compounds 24 and 28 (Table 4), because they shouldn ot be able to interactw ith Asp(3.32). Trp(6.48), His(6.55), and Tyr(7.34) are also involved in the binding of 1 as wella st hat of 2.C ompound 3 also formsahydrogen bond with the main chain of Cys182.…”

Section: Fragmentand Similarity Analysismentioning

confidence: 99%

Structure‐Based Virtual Screening for Dopamine D₂ Receptor Ligands as Potential Antipsychotics

et al. 2016

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Structure-based virtual screening using a D2 receptor homology model was performed to identify dopamine D2 receptor ligands as potential antipsychotics. From screening a library of 6.5 million compounds, 21 were selected and were subjected to experimental validation. From these 21 compounds tested, ten D2 ligands were identified (47.6% success rate, among them D2 receptor antagonists, as expected) that have additional affinity for other receptors tested, in particular 5-HT2A receptors. The affinity (Ki values) of the compounds ranged from 58 nm to about 24 μM. Similarity and fragment analysis indicated a significant degree of structural novelty among the identified compounds. We found one D2 receptor antagonist that did not have a protonatable nitrogen atom, which is a key structural element of the classical D2 pharmacophore model necessary for interaction with the conserved Asp(3.32) residue. This compound exhibited greater than 20-fold binding selectivity for the D2 receptor over the D3 receptor. We provide additional evidence that the amide hydrogen atom of this compound forms a hydrogen bond with Asp(3.32), as determined by tests of its derivatives that cannot maintain this interaction.

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“…A recent effort utilizing a highly-miniaturized 1,536-well assay based on the Quest Fluo-8 calcium detection dye in D 2 and D 3 β-arrestin overexpressing cells resulted in the identification of a novel D 2 DAR antagonist series with excellent D 2 versus D 1 , D 3 , D 4 , and D 5 receptor selectivity that carries the potential for treatment of multiple neuropsychiatric and endocrine disorders. [42,43]…”

Section: High-throughput Screeningmentioning

confidence: 99%

Current approaches for the discovery of drugs that deter substance and drug abuse

Yasgar

Simeonov

2014

Expert Opinion on Drug Discovery

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Introduction Much has been presented and debated on the topic of drug abuse and its multidimensional nature, including the role of society and its customs and laws, economical factors, and the magnitude and nature of the burden. Given the complex nature of the receptors and pathways implicated in regulation of the cognitive and behavioral processes associated with addiction, a large number of molecular targets have been interrogated during recent years to discover starting points for development of small molecule interventions. Areas covered This review describes recent developments in the field of early drug discovery for drug abuse interventions, with a special emphasis on advances published during the 2012-2014 period. Expert Opinion Technologically, the processes/platforms utilized in drug abuse drug discovery are nearly identical to those used in the other disease areas. A key complicating factor in drug abuse research is the enormous biological complexity surrounding the brain processes involved and the associated difficulty in finding “good” targets and achieving exquisite selectivity of treatment agents. While tremendous progress has been made during recent years to use the power of high-throughput technologies to discover proof-of-principle molecules for many new targets, next-generation models will be especially important in this field; examples include seeking advantageous drug-drug combinations, use of automated whole-animal behavioral screening systems, advancing our understanding of the role of epigenetics in drug addiction, and the employment of organoid-level 3D test platforms (also referred to as tissue-chip or organs-on-chip).

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Discovery, Optimization, and Characterization of Novel D₂ Dopamine Receptor Selective Antagonists

Cited by 33 publications

References 30 publications

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

Structure‐Based Virtual Screening for Dopamine D₂ Receptor Ligands as Potential Antipsychotics

Current approaches for the discovery of drugs that deter substance and drug abuse

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Discovery, Optimization, and Characterization of Novel D2 Dopamine Receptor Selective Antagonists

Cited by 33 publications

References 30 publications

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

Structure‐Based Virtual Screening for Dopamine D2 Receptor Ligands as Potential Antipsychotics

Current approaches for the discovery of drugs that deter substance and drug abuse

Contact Info

Product

Resources

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Discovery, Optimization, and Characterization of Novel D₂ Dopamine Receptor Selective Antagonists

Structure‐Based Virtual Screening for Dopamine D₂ Receptor Ligands as Potential Antipsychotics