Non-basic ligands for aminergic GPCRs: The discovery and development diaryl sulfones as selective, orally bioavailable 5-HT2A receptor antagonists for the treatment of sleep disorders

Ladduwahetty, T.; Gilligan, Myra; Humphries, Alexander C.; Merchant, Kevin J.; Fish, R.L.; McAlister, George; Ivarsson, Magnus; Domínguez, María del Carmen; O’Connor, Desmond; MacLeod, Angus M.

doi:10.1016/j.bmcl.2010.04.090

Cited by 11 publications

(8 citation statements)

References 13 publications

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“…It is not likely that the lack of a positively charged group largely reduces the binding affinity between sorafenib and 5-HT 2A , as its binding to 5-HT 2B is at low nanomolar range, where this selectivity may be caused by the other variable binding-site residues like the 5.46 position residue (a serine in 5-HT 2A , while an alanine in 5-HT 2B and 5-HT 2C ) just as the ergoline compounds 70 . This is consistent with a recent report where Ladduwahetty and coworkers discovered novel 5-HT 2A receptor antagonists without containing any positively charged groups 73 . Nevertheless, it is likely that sorafenib can be used as a novel 5-HT 2A lead compound for further structural optimization with maintaining the bi-aryl urea structural moiety.…”

Section: Resultssupporting

confidence: 93%

Life Beyond Kinases: Structure-Based Discovery of Sorafenib as Nanomolar Antagonist of 5-HT Receptors

et al. 2012

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Of great interest in recent years has been computationally predicting the novel polypharmacology of drug molecules. Here, we applied an “induced-fit” protocol to improve the homology models of 5-HT2A receptor, and we assessed the quality of these models in retrospective virtual screening. Subsequently, we computationally screened the FDA approved drug molecules against the best induced-fit 5-HT2A models, and chose six top scoring hits for experimental assays. Surprisingly, one well-known kinase inhibitor, sorafenib has shown unexpected promiscuous 5-HTRs binding affinities, Ki = 1959, 56 and 417 nM against 5-HT2A, 5-HT2B and 5-HT2C, respectively. Our preliminary SAR exploration supports the predicted binding mode, and further suggests sorafenib to be a novel lead compound for 5HTR ligand discovery. Although it has been well known that sorafenib produces anticancer effects through targeting multiple kinases, carefully designed experimental studies are desirable to fully understand whether its “off-target” 5-HTR binding activities contribute to its therapeutic efficacy or otherwise undesirable side effects.

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Section: Resultssupporting

confidence: 93%

Life Beyond Kinases: Structure-Based Discovery of Sorafenib as Nanomolar Antagonist of 5-HT Receptors

et al. 2012

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“…Moreover, lowering the basicity decreased the hERG (IKr) potassium channel's unwanted affinity and improved selectivity. The replacement of central aliphatic piperidine ring by an aromatic moiety such as phenyl [26] or pyridyl [50] led to bis-aryl sulfones with even subnanomolar affinity for the 5-HT 2A R. Another series of nonbasic diaryl sulfones (3-phenylsulfonylcycloalkano[e and d]pyrazolo [1,5-a]pyrimidin-2-yl)amines (Table 1: 5-HT 2A /Cluster 11, 5-HT 2C /Cluster 11) as 5-HT 6/2B receptor ligands was based on the structure of Ro-65-7674-a highly potent and selective 5-HT 6 R antagonist [50].…”

Section: History Of 5-ht 2 R Ligands With Low Basicitymentioning

confidence: 99%

“…5-HT2A/Cluster 8 [37][38][39][40][41]43,45], (80 cmpds) 5-HT2A/Cluster 7 [45], (34 cmpds) pKa=5.44 pKa=8.39 [43] pKa=1.29 pKa=9.68 [58] 5-HT2A/Cluster 11 [26,50], (31 cmpds) 5-HT2A/Cluster 9 [48], (20 cmpds) pKa=0.39 pKa=7.00 [59] pKa=4.23 pKa=6.96 [48] 5-HT2A/Cluster 10 [23,26,49], (15 cmpds) 5-HT2A/Cluster 15 [60], (9 cmpds) pKa=5.88 pKa=7.00 [59] pKa=5.90 pKa=7.33 [61] 5-HT2A/Cluster 5 [62], (8 cmpds) 5-HT2A/Cluster 14 [54], (4 cmpds) pKa=3.35 pKa=8.80 [62] pKa=9.33 pKa=9.55 [63] 5-HT2B/Cluster 16 [33][34][35][36][37], (88 cmpds) 5-HT2B/Cluster 1, 2 [55], (33 cmpds) pKa=5.44 pKa=8.48 [43] pKa=5.47 pKa=9.56 [64] 5-HT2B/Cluster 22 [65] Table 1. Centroids of most populated clusters of nonbasic ligands of 5-HT2A, 5-HT2B, and 5-HT2C receptors and their structurally related basic analogues.…”

Section: History Of 5-ht 2 R Ligands With Low Basicitymentioning

confidence: 99%

“…However, studies on the new groups of serotonin receptor ligands emerging in time revealed that the concept of high basicity was no longer applied to all compounds active towards 5-HTRs, and a number of ligands characterized by low basicity have recently been developed [23][24][25][26][27]. The non-amine structure of ligands is important in terms of developing new drug-like compounds, as it can help in getting rid of side effects.…”

Section: Introductionmentioning

confidence: 99%

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Low Basicity as a Characteristic for Atypical Ligands of Serotonin Receptor 5-HT2

Podlewska

Bugno

Lacivita

et al. 2021

IJMS

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Serotonin receptors are extensively examined by academic and industrial researchers, due to their vital roles, which they play in the organism and constituting therefore important drug targets. Up to very recently, it was assumed that the basic nitrogen in compound structure is a necessary component to make it active within this receptor system. Such nitrogen interacts in its protonated form with the aspartic acid from the third transmembrane helix (D3x32) forming a hydrogen bond tightly fitting the ligand in the protein binding site. However, there are several recent studies that report strong serotonin receptor affinity also for compounds without a basic moiety in their structures. In the study, we carried out a comprehensive in silico analysis of the low-basicity phenomenon of the selected serotonin receptor ligands. We focused on the crystallized representatives of the proteins of 5-HT1B, 5-HT2A, 5-HT2B, and 5-HT2C receptors, and examined the problem both from the ligand- and structure-based perspectives. The study was performed for the native proteins, and for D3x32A mutants. The investigation resulted in the determination of nonstandard structural requirements for activity towards serotonin receptors, which can be used in the design of new nonbasic ligands.

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“…Aryl sulfones are interesting moieties in various fields, including the pharmaceutical industry, agrochemicals, and polymer synthesis. [2][3][4][5][6][7][8] Among these, aryl sulfones and sulfonylated pyridines are highlighted as an important class of versatile and useful compounds. 9,10 Additionally, these pyridines play an important role as directing groups for further functionalization as applied to complex molecule synthesis.…”

mentioning

confidence: 99%

Convenient and Inexpensive Route to Sulfonylated Pyridines via SNAr Reaction of Electron-Rich Pyridines by Iron Catalysis

et al. 2018

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Sulfonylated pyridines were synthesized in moderate to excellent yields, with a wide scope of substituted pyridines and sulfinate salts as starting materials, by an iron-catalyzed SNAr reaction. This new methodology exhibits advantages for the synthesis of these useful substrates, such as the use of a readily available, inexpensive catalyst, prevention of the disproportionation of the sulfinate salts, and, more importantly, providing access to electron-rich pyridine substrates.

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Non-basic ligands for aminergic GPCRs: The discovery and development diaryl sulfones as selective, orally bioavailable 5-HT2A receptor antagonists for the treatment of sleep disorders

Cited by 11 publications

References 13 publications

Life Beyond Kinases: Structure-Based Discovery of Sorafenib as Nanomolar Antagonist of 5-HT Receptors

Life Beyond Kinases: Structure-Based Discovery of Sorafenib as Nanomolar Antagonist of 5-HT Receptors

Low Basicity as a Characteristic for Atypical Ligands of Serotonin Receptor 5-HT2

Convenient and Inexpensive Route to Sulfonylated Pyridines via SNAr Reaction of Electron-Rich Pyridines by Iron Catalysis

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