Design, synthesis, and electrophysiological evaluation of NS6740 derivatives: Exploration of the structure-activity relationship for alpha7 nicotinic acetylcholine receptor silent activation

Pismataro, Maria Chiara; Horenstein, Nicole A.; Stokes, Clare; Quadri, Marta; Amici, Marco De; Papke, Roger L.; Dallanoce, Clelia

doi:10.1016/j.ejmech.2020.112669

Cited by 12 publications

(23 citation statements)

References 50 publications

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“…Finally, the introduction of a nitrile group into the benzyl group of 18 would provide the target molecule 1 . Additional demonstrations for two other drug-like molecules, kwakhurin 47 and α7 nicotinic acetylcholine receptor silent agonist, 48 are shown in Figure 5 c,d and Figure 5 e,f, respectively. To confirm the difference in each step’s score between ReTReK with and without retrosynthesis knowledge, four retrosynthesis knowledge scores were added to each step in the synthetic routes ( Figure S5 ).…”

Section: Resultsmentioning

confidence: 98%

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AI-Driven Synthetic Route Design Incorporated with Retrosynthesis Knowledge

Ishida

Terayama

Kojima

et al. 2022

J. Chem. Inf. Model.

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Computer-aided synthesis planning (CASP) aims to assist chemists in performing retrosynthetic analysis for which they utilize their experiments, intuition, and knowledge. Recent breakthroughs in machine learning (ML) techniques, including deep neural networks, have significantly improved data-driven synthetic route designs without human intervention. However, learning chemical knowledge by ML for practical synthesis planning has not yet been adequately achieved and remains a challenging problem. In this study, we developed a data-driven CASP application integrated with various portions of retrosynthesis knowledge called “ReTReK” that introduces the knowledge as adjustable parameters into the evaluation of promising search directions. The experimental results showed that ReTReK successfully searched synthetic routes based on the specified retrosynthesis knowledge, indicating that the synthetic routes searched with the knowledge were preferred to those without the knowledge. The concept of integrating retrosynthesis knowledge as adjustable parameters into a data-driven CASP application is expected to enhance the performance of both existing data-driven CASP applications and those under development.

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Section: Resultsmentioning

confidence: 98%

“… Comparison of the synthetic route for three target compounds (a,b) hepatitis B virus capsid inhibitor, 45 (c,d) kwakhurin, 47 and (e,f) α7 nicotinic acetylcholine receptor silent agonist 48 ) found by ReTReK with retrosynthesis knowledge (a, c, and e) and the corresponding route found without retrosynthesis knowledge (b, d, and f). …”

Section: Resultsmentioning

confidence: 99%

AI-Driven Synthetic Route Design Incorporated with Retrosynthesis Knowledge

Ishida

Terayama

Kojima

et al. 2022

J. Chem. Inf. Model.

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“…ACh-evoked currents potentiated by GAT107 or B-973B showed reduced calcium permeability, although intracellular calcium was observed to rise [ 91 ]. Silent agonists can overcome this reduced calcium permeability under conditions that do not require ion flux for signaling [ 92 ].…”

Section: Positive Allosteric Modulators (Pams) and Silent Agonists Of The Nachrmentioning

confidence: 99%

“…The combination of nicotine and methyllycaconitine, an α7 nAChR antagonist, result in a form of LTD that can be blocked by dihydro-β-erythroidine. nAChR intervention in nicotine-facilitated synaptic plasticity involves the excitatory glutamatergic synapse [ 92 ]. The nicotine-facilitated LTP in lead-exposed rats is blocked by the NMDA-R antagonist d-(−)-2-amino-5-phosphonopentanoic acid, or picrotoxin, an antagonist of GABA A receptors, leading Wang and coworkers to suggest that nicotine-facilitated synaptic plasticity is due to the activation of NMDARs by presynaptic nAChR-mediated disinhibition of pyramidal cells [ 100 ].…”

Section: Dendritic Spines and Nachr-mediated Synaptic Plasticitymentioning

confidence: 99%

Homomeric and Heteromeric α7 Nicotinic Acetylcholine Receptors in Health and Some Central Nervous System Diseases

Borroni

Barrantes

2021

Membranes

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Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels involved in the modulation of essential brain functions such as memory, learning, and attention. Homomeric α7 nAChR, formed exclusively by five identical α7 subunits, is involved in rapid synaptic transmission, whereas the heteromeric oligomers composed of α7 in combination with β subunits display metabotropic properties and operate in slower time frames. At the cellular level, the activation of nAChRs allows the entry of Na+ and Ca2+; the two cations depolarize the membrane and trigger diverse cellular signals, depending on the type of nAChR pentamer and neurons involved, the location of the intervening cells, and the networks of which these neuronal cells form part. These features make the α7 nAChR a central player in neurotransmission, metabolically associated Ca2+-mediated signaling, and modulation of diverse fundamental processes operated by other neurotransmitters in the brain. Due to its ubiquitous distribution and the multiple functions it displays in the brain, the α7 nAChR is associated with a variety of neurological and neuropsychiatric disorders whose exact etiopathogenic mechanisms are still elusive.

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“…In the last decade, some of us have been active in the study and characterization of α7 nAChRs and their therapeutic potential [16][17][18][19][20][21][22][23][24][25][26]. In this framework, we designed, synthesized and tested (R)-(-)-3-methoxy-1-oxa-2,7-diaza-7,10-ethanospiro [4.5]dec-2-ene sesquifumarate (from now on identified as ICH3), which behaves as a selective orthosteric partial agonist of the α7 receptor subtype [19].…”

Section: Introductionmentioning

confidence: 99%

The Mechanisms Mediated by α7 Acetylcholine Nicotinic Receptors May Contribute to Peripheral Nerve Regeneration

et al. 2021

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Due to the microenvironment created by Schwann cell (SC) activity, peripheral nerve fibers are able to regenerate. Inflammation is the first response to nerve damage and the removal of cellular and myelin debris is essential in preventing the persistence of the local inflammation that may negatively affect nerve regeneration. Acetylcholine (ACh) is one of the neurotransmitters involved in the modulation of inflammation through the activity of its receptors, belonging to both the muscarinic and nicotinic classes. In this report, we evaluated the expression of α7 nicotinic acetylcholine receptors (nAChRs) in rat sciatic nerve, particularly in SCs, after peripheral nerve injury. α7 nAChRs are absent in sciatic nerve immediately after dissection, but their expression is significantly enhanced in SCs after 24 h in cultured sciatic nerve segments or in the presence of the proinflammatory neuropeptide Bradykinin (BK). Moreover, we found that activation of α7 nAChRs with the selective partial agonist ICH3 causes a decreased expression of c-Jun and an upregulation of uPA, MMP2 and MMP9 activity. In addition, ICH3 treatment inhibits IL-6 transcript level expression as well as the cytokine release. These results suggest that ACh, probably released from regenerating axons or by SC themselves, may actively promote through α7 nAChRs activation an anti-inflammatory microenvironment that contributes to better improving the peripheral nerve regeneration.

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Design, synthesis, and electrophysiological evaluation of NS6740 derivatives: Exploration of the structure-activity relationship for alpha7 nicotinic acetylcholine receptor silent activation

Cited by 12 publications

References 50 publications

AI-Driven Synthetic Route Design Incorporated with Retrosynthesis Knowledge

AI-Driven Synthetic Route Design Incorporated with Retrosynthesis Knowledge

Homomeric and Heteromeric α7 Nicotinic Acetylcholine Receptors in Health and Some Central Nervous System Diseases

The Mechanisms Mediated by α7 Acetylcholine Nicotinic Receptors May Contribute to Peripheral Nerve Regeneration

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