Discovery of substituted (4-phenyl-1H-imidazol-2-yl)methanamine as potent somatostatin receptor 3 agonists

Lai, Zhong; He, Shuwen; Sherer, Edward C.; Wu, Zhicai; Yu, Yang; Ball, Richard G.; Hong, Qingmei; Yang, David; Guo, Liangqing; Li, Derun; Tuang, Quang; Chicchi, Gary G.; Trusca, Dorina; Tsao, Kwei-Lan; Zhou, Yunping; Howard, Andrew D.; Nargund, Ravi P.

doi:10.1016/j.bmcl.2015.06.087

Cited by 2 publications

(9 citation statements)

References 15 publications

(12 reference statements)

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“…S3‐5p with a quinoline substitution has a low activity of 5.85. Lai et al 34 reported that the addition of a bulky group like branched five‐membered heterocycles of MK‐4256 at the position provides a needed steric projection from the pharmacophore of more conserved agonist, which correlates well with our results. They also reported that the modification of phenyl to a much bulkier quinolone in certain SSTR3 ligands has significantly increased their agonism by four times.…”

Section: Resultssupporting

confidence: 90%

“…As the templates and SSTR3 share significant sequence identity (>40%) and are part of the same structural family (GPCR), it is plausible to consider them to have comparable biological functions. Substituted (4‐phenyl‐1H‐imidazol‐2‐yl) methenamine reported as SSTR3 ligands 34 were docked with the predicted model of SSTR3 using Surflex docking algorithm in Sybyl‐X 2.1. Compound 5c was reported as highly potent low molecular weight agonist in the literature.…”

Section: Resultsmentioning

confidence: 99%

“…Compounds 5a , 5b , and 5c with a phenyl substitution at R4 showed low activities comparatively. Lai et al 34 reported that the introduction of polarity in the form of cyclohexyl to piperidine resulted in a potency loss. Compounds with halogen groups like 5f and 5i with CF3, 5h with Cl and 5k with a fluorine atom showed lesser activities compared to high active compounds.…”

Section: Resultsmentioning

confidence: 99%

“…Lai et al 34 discovered substituted (4‐phenyl‐1H‐imidazol‐2‐yl) methanamine as potent SSTR3 agonists, which are represented in Table S1. A common scaffold was identified for the dataset, and the molecules were modeled using Sybyl‐X 2.1.…”

Section: Methodsmentioning

confidence: 99%

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Structure and dynamics of the somatostatin receptor 3‐ligand binding in the presence of lipids examined using computational structural biology methods

et al. 2021

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In the past two decades, the structural biology studies on G‐protein coupled receptors (GPCRs) are on the rise. Understanding the relation between the structure and function of GPCRs is important as they play a huge role in various signaling mechanisms in a eukaryotic cell. Somatostatin receptor 3 (SSTR3), one of the GPCRs, is one such important receptor which oversees different cellular processes including cell‐to‐cell signaling. However, the information available regarding the structural features of SSTR3 responsible for their bioactivity is scarce. In this study, we report a structural understanding of SSTR3‐ligand binding that could be helpful in demystifying the structural complexities related to functioning of the receptor. An integrated protocol consisting of different computational structural biology tools including protein structure prediction via comparative modeling, binding site characterization, three‐dimensional quantitative structure–activity relationship based on comparative molecular field analysis and comparative molecular similarity indices analysis, density functional theory, and molecular dynamics simulations were performed. Different understandings from the simulation of SSTR3‐ligand complexes, mainly the conditions that are favorable for the formation of lowest bioactive state of SSTR3 ligands are reported. In addition to that, we report the important physicochemical descriptors of SSTR3 ligands that could significantly influence their bioactivity. The results of the study could be helpful in developing novel SSTR3 ligands (both agonists and antagonists) with high potency and receptor selectivity.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Structure and dynamics of the somatostatin receptor 3‐ligand binding in the presence of lipids examined using computational structural biology methods

et al. 2021

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“…However, development was discontinued due to adverse cardiovascular effects related to human ether-a-go-go–related gene off-target side effects ( He et al, 2014 ). Attempts to eliminate this off-target action have led to discovery of (4-phenyl-1 H -imidazol-2-yl)-methanamines as potent and selective SST 3 agonists ( Li et al, 2014 ; Lai et al, 2015 ).…”

Section: Somatostatin Receptormentioning

confidence: 99%

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

et al. 2018

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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.

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Discovery of substituted (4-phenyl-1H-imidazol-2-yl)methanamine as potent somatostatin receptor 3 agonists

Cited by 2 publications

References 15 publications

Structure and dynamics of the somatostatin receptor 3‐ligand binding in the presence of lipids examined using computational structural biology methods

Structure and dynamics of the somatostatin receptor 3‐ligand binding in the presence of lipids examined using computational structural biology methods

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

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