Identification of dual role of piperazine-linked phenyl cyclopropyl methanone as positive allosteric modulator of 5-HT2C and negative allosteric modulator of 5-HT2B receptors

Singh, Kartikey; Sona, Chandan; Ojha, Vikash; Singh, M. P.; Mishra, Ankita; Kumar, Abdhesh; Siddiqi, Mohammad Imran; Tripathi, Rama Pati; Yadav, Prem N.

doi:10.1016/j.ejmech.2018.12.070

Cited by 18 publications

(17 citation statements)

References 39 publications

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“…The latest 5-HT 2C R PAM in this trio is 26 which was reported by Yadav and colleagues in 2019 (Fig. 9) [143]. This work identifies a phenyl cyclopropyl-linked N -heterocycle pharmacophore as producing multiple derivatives with PAM activity at the 5-HT 2C R and one compound ( 26 ) with additional NAM activity at the 5-HT 2B R. Robust SAR studies were reported for their scaffold of interest, however the origin of this pharmacophore and the rationale for designing N -heterocycle compounds as potential 5-HT 2C R PAMs was not fully disclosed.…”

Section: The Current State Of 5-ht2cr Positive Allosteric Modulatorsmentioning

confidence: 70%

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Targeting the 5-HT2C Receptor in Biological Context and the Current State of 5-HT2C Receptor Ligand Development

Wold

Wild

Cunningham

et al. 2019

CTMC

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Serotonin (5-HT) 5-HT2C receptor (5-HT2CR) is recognized as a critical mediator of disease-related pathways and behaviors based upon actions in the central nervous system (CNS). Since 5-HT2CR is a class A G protein-coupled receptor (GPCR), drug discovery efforts have traditionally pursued the activation of the receptor through synthetic ligands with agonists proposed for the treatment of obesity, substance use disorders and impulse control disorders while antagonists may add value for the treatment of anxiety, depression and schizophrenia. The most significant agonist discovery to date is the FDA-approved anti-obesity medication lorcaserin. In recent years, efforts towards developing other mechanisms to enhance receptor function have resulted in the discovery of Positive Allosteric Modulators (PAMs) for the 5-HT2CR, with several molecule series now reported. The biological significance and context for signaling and function of the 5-HT2CR, and the current status of 5-HT2CR agonists and PAMs are discussed in this review.

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Section: The Current State Of 5-ht2cr Positive Allosteric Modulatorsmentioning

confidence: 70%

“…The lead compounds from recent 5-HT 2C R PAM discovery projects include VA012 ( 25 ) [142], 26 [143], and CYD-1–79 ( 27 ) [121] respectively. The CLogPs are reported to demonstrate that elevated lipophilicity is common among these newly discovered 5-HT 2C R PAMs.…”

Section: Fig (1)mentioning

confidence: 99%

Targeting the 5-HT2C Receptor in Biological Context and the Current State of 5-HT2C Receptor Ligand Development

Wold

Wild

Cunningham

et al. 2019

CTMC

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“…Recently, imidazole linked phenyl cyclopropyl methanones were shown to display PAM activity on both 5-HT 2C and 5-HT 2B receptors. Furthermore, piperazine linked phenyl cyclopropyl methanones were active as PAM at 5-HT 2C (increased the Emax of serotonin), and as negative allosteric modulator (NAM) at 5-HT 2B receptors (decreases EC50 of serotonin 10 times without affecting Emax) (69). The identification of specific PAMs at 5-HT 2B receptors may conceivably lead to improved therapeutics.…”

Section: Allosteric Modulatorsmentioning

confidence: 99%

Gene Structure, Expression, and 5-HT2B Receptor Signaling

Maroteaux

2021

5-Ht2b Receptors

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Although the contractile effects of serotonin on stomach has been described since long time, the identification of the receptor mediating such a response was only obtained by molecular cloning in 1992. The pharmacological characterization of the 5-HT 2B receptor subtype in various species identified proximity but differences in its pharmacology, as compared to 5-HT 2A or 5-HT 2C receptors. Initially thought to be restricted in periphery, 5-HT 2B receptor expression was also detected in various cell types in the central nervous system. Although quite low at adult stage, a strong expression of 5-HT 2B receptors has been found early in embryos in migrating neural crest cells, neural tube, hematopoietic tissue, and heart primordia. In this chapter, we will develop and discuss the complexity of its signaling in relation with its expression, including in various types of cancer cells.

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“…A piperazine-linked phenyl cyclopropyl methanone was found by Singh et al (2019) to be a positive allosteric modulator of 5-HT 2C and negative allosteric modulator of 5-HT 2B receptors [95]. This compound (58 in Singh et al (2019) [95]), as a positive allosteric modulator of 5-HT 2C , increases the E max of 5-HT to 139%, and as a negative allosteric modulator of 5-HT 2B , decreases the EC 50 of 5-HT 10 times without affecting the E max . Molecular docking studies revealed that this allosteric compound binds to the predicted allosteric site on 5-HT 2B [135,136] and 5-HT 2C receptors [142].…”

Section: Exogenous Allosteric Modulator Of Serotonin Receptorsmentioning

confidence: 99%

Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics

et al. 2020

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Schizophrenia was first described by Emil Krapelin in the 19th century as one of the major mental illnesses causing disability worldwide. Since the introduction of chlorpromazine in 1952, strategies aimed at modifying the activity of dopamine receptors have played a major role for the treatment of schizophrenia. The introduction of atypical antipsychotics with clozapine broadened the range of potential targets for the treatment of this psychiatric disease, as they also modify the activity of the serotoninergic receptors. Interestingly, all marketed drugs for schizophrenia bind to the orthosteric binding pocket of the receptor as competitive antagonists or partial agonists. In recent years, a strong effort to develop allosteric modulators as potential therapeutic agents for schizophrenia was made, mainly for the several advantages in their use. In particular, the allosteric binding sites are topographically distinct from the orthosteric pockets, and thus drugs targeting these sites have a higher degree of receptor subunit specificity. Moreover, “pure” allosteric modulators maintain the temporal and spatial fidelity of native orthosteric ligand. Furthermore, allosteric modulators have a “ceiling effect”, and their modulatory effect is saturated above certain concentrations. In this review, we summarize the progresses made in the identification of allosteric drugs for dopamine and serotonin receptors, which could lead to a new generation of atypical antipsychotics with a better profile, especially in terms of reduced side effects.

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Identification of dual role of piperazine-linked phenyl cyclopropyl methanone as positive allosteric modulator of 5-HT2C and negative allosteric modulator of 5-HT2B receptors

Cited by 18 publications

References 39 publications

Targeting the 5-HT2C Receptor in Biological Context and the Current State of 5-HT2C Receptor Ligand Development

Targeting the 5-HT2C Receptor in Biological Context and the Current State of 5-HT2C Receptor Ligand Development

Gene Structure, Expression, and 5-HT2B Receptor Signaling

Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics

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