SAR and biological evaluation of SEN12333/WAY-317538: Novel alpha 7 nicotinic acetylcholine receptor agonist

Haydar, Simon N.; Ghiron, Chiara; Bettinetti, Laura; Bothmann, Hendrick; Comery, Thomas A.; Dunlop, John; Rosa, Salvatore La; Micco, Iolanda; Pollastrini, Martina; Quinn, Joanna; Roncarati, Renza; Scali, Carla; Valacchi, Michela; Varrone, Maurizio; Zanaletti, Riccardo

doi:10.1016/j.bmc.2009.05.040

Cited by 39 publications

(46 citation statements)

References 12 publications

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“…In the last years both α7nAchRs agonist [35,[52][53][54] and also several antagonist have been described to ameliorate AD pathology [35,53,55] and since nAChRs are ligand-gated ion channels critical for learning and memory and involved in the development of AD [7,56], the results presented here indicate that gymnodimine may constitute a valuable compound to design new diseasemodifying drugs in Alzheimer´s disease and related neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 91%

The Cholinergic Antagonist Gymnodimine Improves Aβ and Tau Neuropathology in an <i>in Vitro</i> Model of Alzheimer Disease

Albrecht¹,

Vale²,

Vieytes³

et al. 2011

Cell Physiol Biochem

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Gymnodimine (GYM) is a marine phycotoxin with a macrocyclic imine structure, isolated from extracts of the dinoflagellate Karenia selliformis known to act as a cholinergic antagonist with subtype selectivity. However, no data on the chronic effects of this compound has been reported so far. In this work, we evaluated the effect of long term exposure of cortical neurons to gymnodimine in the progress of Alzheimer disease (AD) pathology in vitro. Treatment of cortical neurons with 50 nM gymnodimine decreased the intracellular amyloid beta (Aβ) accumulation and the levels of the hyperphosphorylated isoforms of tau protein recognized by AT8 and AT100 antibodies. These results are suggested to be mediated by the increase in the inactive isoform of the glycogen synthase kinase-3 (phospho GSK-3 Ser9), the decrease in the levels of the active isoform of the ERK1/2 kinase and the increase in acetylcholine (Ach) synthesis elicited by long term exposure of cortical neurons to the toxin. Moreover, gymnodimine decreased glutamate-induced neurotoxicity in vitro. Altogether these results indicate that the marine phycotoxin gymnodimine may constitute a valuable tool for the development of drugs to treat neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 91%

The Cholinergic Antagonist Gymnodimine Improves Aβ and Tau Neuropathology in an <i>in Vitro</i> Model of Alzheimer Disease

Albrecht¹,

Vale²,

Vieytes³

et al. 2011

Cell Physiol Biochem

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“…[2] Two pharmacophores have been recognized in acetylcholine (ACh), a nonbonding electron pair providing hydrogen bonding to the receptor and a positively charged nitrogen center responsible for a cation-p interaction. [1,3] Ionized nicotine mimics ACh, but the N···N distance between the recognition sites is conformer-dependent.…”

Section: Introductionmentioning

confidence: 99%

The Conformational Landscape of Nicotinoids: Solving the Conformational Disparity of Anabasine

Lesarri

Cocinero

Evangelisti

et al. 2010

Chemistry A European J

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The conformational landscape of the alkaloid anabasine (neonicotine) has been investigated by using rotational spectroscopy and ab initio calculations. The results allow a detailed comparison of the structural properties of the prototype piperidinic and pyrrolidinic nicotinoids (anabasine vs. nicotine). Anabasine adopts two most stable conformations in isolation conditions, for which we determined accurate rotational and nuclear quadrupole coupling parameters. The preferred conformations are characterized by an equatorial pyridine moiety and additional N-H equatorial stereochemistry at the piperidine ring (eq-eq; eq=equatorial). The two rings of anabasine are close to a bisecting arrangement, with the observed conformations differing by an approximately 180 degrees rotation of the pyridine subunit, denoted either syn or anti. The preference of anabasine for the eq-eq-syn conformation has been established by relative intensity measurements (syn/anti approximately 5(2)). The conformational preferences of free anabasine are directed by a weak N...H-C hydrogen bond interaction between the nitrogen lone pair at piperidine and the closest C-H bond in pyridine, with N...H distances ranging from 2.686 (syn) to 2.667 A (anti). Supporting ab initio calculations by using MP2 and the recent M05-2X density functional are provided, evaluating the predictive performance of both methods.

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“…SEN12333/WAY-317538 (28) was evaluated in in vivo efficacy models based on its generally good in vitro profile (α7 nAChR K i ¼ 260 nM, EC 50 ¼ 1.65 μM), ease of synthesis, and selectivity on a related panel of nicotinic (α1*,α3*,α4β2) and highly homologous 5HT 3 ARs [168]. When the compound was tested at 10 μM in a panel of $70 binding sites including all major classes of neurotransmitter, growth factor, and peptide receptors, no significant activity was observed except at the histamine H 3 receptor, where binding was observed leading to receptor antagonism.…”

Section: α7 Nachr Agonists For Schizophreniamentioning

confidence: 99%

Nicotinic Acetylcholine Receptor Modulators

Mazurov¹,

Yohannes

2014

Small Molecule Therapeutics for Schizophrenia

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Nicotine and its pharmacology have long been associated with schizophrenia and its epidemiology and treatment. Schizophrenics use nicotine in its major delivery form of cigarettes at a significantly higher incidence than the general population (80-90% vs. 25-30% of the general population) and even than those diagnosed with other psychiatric diseases. Various studies have demonstrated that cigarette smoking transiently restores cognitive and sensory deficits in patients with schizophrenia/schizoaffective disorders. Conversely, smoking cessation appears to exacerbate the symptoms of the disease. A disturbance of nicotinic receptor expression, affecting the α7 and α4β2 subunits, in various cerebral areas has been revealed in postmortem binding studies. Genetic linkage studies have also demonstrated that the α7 subunit is involved in the pathology of schizophrenia. Much of the drug discovery and development efforts in the nAChR field have focused on α7 and α4β2 nAChR subtypes. These include studies using nicotine and varenicline (the smoking cessation drug marketed as Chantix or Champix) as well as numerous other small-molecule therapeutics targeting these receptor subtypes. While some early studies included α4β2 modulators, the large majority of drug development of nAChR ligands for schizophrenia have been α7 agonists and partial agonists. Such therapeutics are in late-stage development and may constitute a breakthrough for the treatment of schizophrenia with safe and effective medicines.

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SAR and biological evaluation of SEN12333/WAY-317538: Novel alpha 7 nicotinic acetylcholine receptor agonist

Cited by 39 publications

References 12 publications

The Cholinergic Antagonist Gymnodimine Improves Aβ and Tau Neuropathology in an <i>in Vitro</i> Model of Alzheimer Disease

The Cholinergic Antagonist Gymnodimine Improves Aβ and Tau Neuropathology in an <i>in Vitro</i> Model of Alzheimer Disease

The Conformational Landscape of Nicotinoids: Solving the Conformational Disparity of Anabasine

Nicotinic Acetylcholine Receptor Modulators

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