SAR of the arylpiperazine moiety of obeline somatostatin sst1 receptor antagonists

Hurth, Konstanze; Enz, Albert; Gentsch, C.; Hoyer, Daniel; Langenegger, Daniel; Neumann, Peter; Pfäffli, Paul; Sorg, Dieter; Swoboda, Robert; Vassout, A.; Troxler, Thomas

doi:10.1016/j.bmcl.2007.04.078

Cited by 9 publications

(14 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The presence of bulky group substitutions in compounds like 6 , 8 , and 13 could be responsible for their low activity. In the case of compounds 47 – 55 , Hurth et al 28 replaced the piperazine ring with homopiperazine, tetrahydropyridine ring, and some other moieties, but it resulted in a significant loss of activity. The presence of a yellow contour near the region indicates the fact that the bulky atom substituent at this position is not favorable for the activity.…”

Section: Resultsmentioning

confidence: 99%

“…Hurth et al 28 reported that going for a 2-pyridone substituent instead of 2-pyridine, with a N -methyl substitution, resulted in increased activity and more than 6000-fold selectivity for SSTR1 over SSTR2. The presence of a white contour near this substitution position supports the result reported by Hurth et al 28 Compound 9 with an NH instead of N -methyl at this position has comparatively lesser activity and SSTR1 selectivity than compound 10 . Hurth et al also reported that the presence of more wettable atoms like hydroxy, carbonyl, carboxyl, sulfonyl, and sulfonamide at 4′ in compounds 34 – 41 respectively is less favorable for their activity.…”

Section: Resultsmentioning

confidence: 99%

“…This fact is confirmed in other studies related to obeline derivatives reported by the same group. 28 , 29 …”

Section: Resultsmentioning

confidence: 99%

“… 30 reported that removal or replacing of the N -methyl substituent of the 2-bromo-ergoline core, in compounds 87 – 91 , with longer alkyl groups resulted in a significant loss of SSTR1 activity. Based on the SAR analysis of substituted phenylpiperazines by Hurth et al, 28 the presence of an electronegative atom like 2′F or 2′cyano is not favorable for activity, whereas the introduction of a nitro atom at these positions greatly increases the SSTR1 affinity. χ analysis of molecules with these substituents supported this result.…”

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Molecular-Level Understanding of the Somatostatin Receptor 1 (SSTR1)–Ligand Binding: A Structural Biology Study Based on Computational Methods

et al. 2020

View full text Add to dashboard Cite

Somatostatin receptor 1 (SSTR1), a subtype of somatostatin receptors, is involved in various signaling mechanisms in different parts of the human body. Like most of the G-protein-coupled receptors (GPCRs), the available information on the structural features of SSTR1 responsible for the biological activity is scarce. In this study, we report a molecular-level understanding of SSTR1–ligand binding, which could be helpful in solving the structural complexities involved in SSTR1 functioning. Based on a three-dimensional quantitative structure–activity relationship (3D-QSAR) study using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), we have identified that an electronegative, less-bulkier, and hydrophobic atom substitution can substantially increase the biological activity of SSTR1 ligands. A density functional theory (DFT) study has been followed to study the electron-related properties of the SSTR1 ligands and to validate the results obtained via the 3D-QSAR study. 3D models of SSTR1–ligand systems have been embedded in lipid–lipid bilayer membranes to perform molecular dynamics (MD) simulations. Analysis of the MD trajectories reveals important information about the crucial residues involved in SSTR1–ligand binding and various conformational changes in the protein that occur after ligand binding. Additionally, we have identified the probable ligand-binding site of SSTR1 and validated it using MD. We have also studied the favorable conditions that are essential for forming the most stable and lowest-energy bioactive conformation of the ligands inside the binding site. The results of the study could be useful in constructing more potent and novel SSTR1 antagonists and agonists.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…This fact is confirmed in other studies related to obeline derivatives reported by the same group. 28 , 29 …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Molecular-Level Understanding of the Somatostatin Receptor 1 (SSTR1)–Ligand Binding: A Structural Biology Study Based on Computational Methods

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Consistent with the inhibitory autoreceptor role of SST 1 , SRA880 administration increases SRIF brain release and signaling, countering depressive-like symptoms in mice ( Nilsson et al, 2012 ). A series of SST 1 -selective ergoline derivatives has been developed, some of which show effective oral bioavailability and brain penetration ( Hurth et al, 2007 ; Troxler et al, 2008 ). The only clinically approved SRIF analog showing high affinity for SST 1 is pasireotide, a nonselective peptidic compound displaying an IC 50 of 9.3 nM for SST 1 , and IC 50 values for SST 2 , SST 3 , and SST 5 of 1, 1.5, and 0.16 nM, respectively ( Schmid, 2008 ).…”

Section: Somatostatin Receptormentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

et al. 2018

View full text Add to dashboard Cite

Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein–coupled receptors (GPCRs) called somatostatin receptor (SST)1–5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.

show abstract

Bicyclic 5-6 Systems: Four Heteroatoms 3:1

Barbero¹,

Díez-Poza²,

Fernández‐Peña³

et al. 2022

Comprehensive Heterocyclic Chemistry IV

View full text Add to dashboard Cite

SAR of the arylpiperazine moiety of obeline somatostatin sst1 receptor antagonists

Cited by 9 publications

References 9 publications

Molecular-Level Understanding of the Somatostatin Receptor 1 (SSTR1)–Ligand Binding: A Structural Biology Study Based on Computational Methods

Molecular-Level Understanding of the Somatostatin Receptor 1 (SSTR1)–Ligand Binding: A Structural Biology Study Based on Computational Methods

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

Bicyclic 5-6 Systems: Four Heteroatoms 3:1

Contact Info

Product

Resources

About