Effects of EGIS-7625, a Selective and Competitive 5-HT<sub>2B</sub>Receptor Antagonist

Kovács, Anikó; Szikora, István; Wellmann, J.; Schmidt, Éva; Szücs, Z; Dubreuil, Valérie; Nicolas, Jean Paul; Boutin, Jean A.; Bozsing, D.; Egyed, András; Tihanyi, Károly; Spedding, Michael; Szénási, Gábor

doi:10.1023/b:card.0000015857.96371.43

Cited by 6 publications

(2 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The chemical space of known 5-HT 2B R ligands might be represented by a couple of chemotypes (presented in Figure 1 ). Examples of high affinity 5-HT 2B R compounds showing selectivity against 5-HT 1B R are represented by triazines ( 1 ) [ 21 ], piperidines ( 2 , 3 ), pyrimidines (e.g., RS-127445 ( 4 )) [ 22 ], arylpiperazines (m-CPP [ 23 ], EGIS-7625 ( 5 ) [ 24 ]), tetrahydro-β-carbolines (LY-23728 ( 6 ), LY-272015, LY-266097) [ 25 ], and aryl ureas (SB-200646A ( 7 ), SB-204741, SB-215505) [ 26 ]. Interestingly, the contribution of in silico methods to the discovery of novel 5-HT 2B R ligands is rather limited [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Fingerprint-Based Machine Learning Approach to Identify Potent and Selective 5-HT2BR Ligands

et al. 2018

View full text Add to dashboard Cite

The identification of subtype-selective GPCR (G-protein coupled receptor) ligands is a challenging task. In this study, we developed a computational protocol to find compounds with 5-HT2BR versus 5-HT1BR selectivity. Our approach employs the hierarchical combination of machine learning methods, docking, and multiple scoring methods. First, we applied machine learning tools to filter a large database of druglike compounds by the new Neighbouring Substructures Fingerprint (NSFP). This two-dimensional fingerprint contains information on the connectivity of the substructural features of a compound. Preselected subsets of the database were then subjected to docking calculations. The main indicators of compounds’ selectivity were their different interactions with the secondary binding pockets of both target proteins, while binding modes within the orthosteric binding pocket were preserved. The combined methodology of ligand-based and structure-based methods was validated prospectively, resulting in the identification of hits with nanomolar affinity and ten-fold to ten thousand-fold selectivities.

show abstract

Section: Introductionmentioning

confidence: 99%

Fingerprint-Based Machine Learning Approach to Identify Potent and Selective 5-HT2BR Ligands

et al. 2018

View full text Add to dashboard Cite

show abstract

“…3) is another selective 5-HT 2B ligand that can be used to explore the therapeutic value of 5-HT 2B antagonism [58]. …”

Section: Cardiovascular Systemmentioning

confidence: 99%

Emerging Opportunities and Concerns for Drug Discovery at Serotonin 5-5-HT2B Receptors

Brea¹,

Castro‐Palomino²,

Yeste³

et al. 2010

CTMC

View full text Add to dashboard Cite

5-HT(2B) receptors have been reported to play an important role at cardiac, intestinal and central levels, as well as in bone marrow formation and growth. In the last decade, 5-HT(2B) receptors have also gained much attention as new targets in therapeutics, but also as off-targets because their activation along with the inhibition of serotonin transporters plays a significant role in the pathogenesis of 5-HT induced valvulopathy. Taking this into account, the present review focuses on the new therapeutic applications of 5-HT(2B) receptor ligands as well as on the potential concerns.

show abstract

Aryl Biphenyl‐3‐ylmethylpiperazines as 5‐HT₇ Receptor Antagonists

Kim

Tae

et al. 2013

ChemMedChem

View full text Add to dashboard Cite

The 5-HT7 receptor (5-HT7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7 R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7 R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7 R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7 R. Among the synthesized compounds, 1-([2'-methoxy-(1,1'-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28) was the best binder to the 5-HT7 R (pKi =7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7 R over other serotonin receptor subtypes, such as 5-HT1 R, 5-HT2 R, 5-HT3 R, and 5-HT6 R. In a molecular modeling study, the 2-methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function.

show abstract

Effects of EGIS-7625, a Selective and Competitive 5-HT_2BReceptor Antagonist

Cited by 6 publications

References 19 publications

Fingerprint-Based Machine Learning Approach to Identify Potent and Selective 5-HT2BR Ligands

Fingerprint-Based Machine Learning Approach to Identify Potent and Selective 5-HT2BR Ligands

Emerging Opportunities and Concerns for Drug Discovery at Serotonin 5-5-HT2B Receptors

Aryl Biphenyl‐3‐ylmethylpiperazines as 5‐HT₇ Receptor Antagonists

Contact Info

Product

Resources

About

Effects of EGIS-7625, a Selective and Competitive 5-HT2BReceptor Antagonist

Cited by 6 publications

References 19 publications

Fingerprint-Based Machine Learning Approach to Identify Potent and Selective 5-HT2BR Ligands

Fingerprint-Based Machine Learning Approach to Identify Potent and Selective 5-HT2BR Ligands

Emerging Opportunities and Concerns for Drug Discovery at Serotonin 5-5-HT2B Receptors

Aryl Biphenyl‐3‐ylmethylpiperazines as 5‐HT7 Receptor Antagonists

Contact Info

Product

Resources

About

Effects of EGIS-7625, a Selective and Competitive 5-HT_2BReceptor Antagonist

Aryl Biphenyl‐3‐ylmethylpiperazines as 5‐HT₇ Receptor Antagonists