F17464 a New Antipsychotic With Preferential D3 Antagonist, 5-HT1A Partial Agonist Properties. Neurochemical Studies

ABSTRACT Introduction: Pacific people in New Zealand have one of the highest rates of smoking. Cytisine is a plant-based alkaloid that has proven efficacy, effectiveness and safety compared to a placebo and nicotine replacement therapy (NRT) for smoking cessation. Cytisine, like varenicline, is a partial agonist of nicotinic acetylcholine receptors, and blocks the rewarding effects of nicotine. Cytisine is naturally found in some plants in the Pacific region, and so may appeal to Pacific smokers wanting to quit. This paper investigates the acceptability of cytisine as a smoking cessation product for Pacific smokers in New Zealand, using a qualitative study design. Methods: In December 2015, advertisements and snowball sampling was used to recruit four Pacific smokers and three Pacific smoking cessation specialists in Auckland, New Zealand. Semi-structured interviews where undertaken, whereby participants were asked about motivations to quit and their views on smoking cessation products, including cytisine (which is currently unavailable in New Zealand). Interviews were recorded and transcribed verbatim, with thematic analysis conducted manually. Findings: Pacific smokers reported wanting to quit for loved ones and family, but did not find currently available smoking cessation products effective. Almost all participants had not previously heard of cytisine, but many of the Pacific smokers were keen to try it. Participants identified with cytisine on a cultural basis (given its natural status), but noted that their use would be determined by the efficacy of the medicine, its cost, side-effects, and accessibility. They were particularly interested in cytisine being made available in liquid form, which could be added to a “smoothie” or drunk as a “traditional tea”. Participants thought cytisine should be promoted in a culturally-appropriate way, with packaging and advertising designed to appeal to Pacific smokers. Conclusions: Cytisine is more acceptable to Pacific smokers than other smoking cessation products, because of their cultural practices of traditional medicine and the natural product status of cytisine.

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The Study of a Selective Serotonin Partial Agonist and Reuptake Inhibitors, HEC113995PA•H2O,in Healthy Subjects

Case Medical Research ◽

10.31525/ct1-nct03943251 ◽

2019 ◽

Author(s):

Keyword(s):

Healthy Subjects ◽

Partial Agonist ◽

Selective Serotonin

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In silico Discovery of Resveratrol Analogues as Potential Agents in Treatment of Metabolic Disorders

Current Pharmaceutical Design ◽

10.2174/1381612825666191029095252 ◽

2019 ◽

Vol 25 (35) ◽

pp. 3776-3783

Author(s):

Nebojša Pavlović ◽

Maja Đanić ◽

Bojan Stanimirov ◽

Svetlana Goločorbin-Kon ◽

Karmen Stankov ◽

...

Keyword(s):

In Silico ◽

Metabolic Disorders ◽

Partial Agonist ◽

Aqueous Solubility ◽

Structural Similarity ◽

Data Bank ◽

Docking Studies ◽

Binding Energies ◽

Molegro Virtual Docker ◽

Ppar Γ

Background: Resveratrol was demonstrated to act as partial agonist of PPAR-γ receptor, which opens up the possibility for its use in the treatment of metabolic disorders. Considering the poor bioavailability of resveratrol, particularly due to its low aqueous solubility, we aimed to identify analogues of resveratrol with improved pharmacokinetic properties and higher binding affinities towards PPAR-γ. Methods: 3D structures of resveratrol and its analogues were retrieved from ZINC database, while PPAR-γ structure was obtained from Protein Data Bank. Docking studies were performed using Molegro Virtual Docker software. Molecular descriptors relevant to pharmacokinetics were calculated from ligand structures using VolSurf+ software. Results: Using structural similarity search method, 56 analogues of resveratrol were identified and subjected to docking analyses. Binding energies were ranged from -136.69 to -90.89 kcal/mol, with 16 analogues having higher affinities towards PPAR-γ in comparison to resveratrol. From the calculated values of SOLY descriptor, 23 studied compounds were shown to be more soluble in water than resveratrol. However, only two tetrahydroxy stilbene derivatives, piceatannol and oxyresveratrol, had both better solubility and affinity towards PPAR-γ. These compounds also had more favorable ADME profile, since they were shown to be more metabolically stable and wider distributed in body than resveratrol. Conclusion: Piceatannol and oxyresveratrol should be considered as potential lead compounds for further drug development. Although experimental validation of obtained in silico results is required, this work can be considered as a step toward the discovery of new natural and safe drugs in treatment of metabolic disorders.

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Does the Oxazolidinone Derivatives Constitute a Functional Approach for Cancer Therapy?

Clinical Cancer Drugs ◽

10.2174/2212697x07999200807210936 ◽

2020 ◽

Vol 7 (2) ◽

pp. 95-106

Author(s):

Eduardo Augusto Vasconcelos de Freitas Ramalho ◽

Marina Galdino da Rocha Pitta ◽

Hernando de Barros Siqueira Neto ◽

Ivan da Rocha Pitta

Keyword(s):

Cell Lines ◽

Antitumor Agents ◽

Partial Agonist ◽

Drug Repurposing ◽

Antitumor Agent ◽

Short Review ◽

Sphingolipid Metabolism ◽

Solid Cancer ◽

Ppar Γ ◽

Anti Cancer

In the last four decades, the emphasis was laid on the research of small organic molecules with potential anti-cancer activity. Linezolid was the first oxazolidinone derivative approved by FDA for MRSA treatment. Despite its major role in antimicrobial activity, these molecules display other properties, also serving as an antitumor agent. The importance of drug repurposing could be highlighted by the use of Oxazolidinone derivatives in pre-clinical studies, which are able to act through different pathways, such as partial agonist of transcription factor PPAR-γ, an inhibitor of key enzymes related to hormone-dependent disorders and even on sphingolipid metabolism as well. The purpose of this short review is to discuss the application of oxazolidinone derivatives as an antitumor agent by highlighting the most promising molecules studied by many research groups worldwide. Main biological activity against several tumor cell lines, including hematopoietic and solid cancer cell lines have been discussed. In addition, this study intends to report how different types of oxazolidinone derivatives can act as antitumor agents describing their distinct mechanisms of action based on their targets.

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Melatonin MT1 and MT2 Receptors Exhibit Distinct Effects in the Modulation of Body Temperature across the Light/Dark Cycle

International Journal of Molecular Sciences ◽

10.3390/ijms20102452 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2452 ◽

Cited By ~ 8

Author(s):

Martha López-Canul ◽

Seung Hyun Min ◽

Luca Posa ◽

Danilo De Gregorio ◽

Annalida Bedini ◽

...

Keyword(s):

Body Temperature ◽

Receptor Antagonist ◽

Partial Agonist ◽

Receptor Subtypes ◽

Dark Phase ◽

Light Phase ◽

Dark Cycle ◽

Simultaneous Activation ◽

Type 3 ◽

G Protein Coupled

Melatonin (MLT) is a neurohormone that regulates many physiological functions including sleep, pain, thermoregulation, and circadian rhythms. MLT acts mainly through two G-protein-coupled receptors named MT1 and MT2, but also through an MLT type-3 receptor (MT3). However, the role of MLT receptor subtypes in thermoregulation is still unknown. We have thus investigated the effects of selective and non-selective MLT receptor agonists/antagonists on body temperature (Tb) in rats across the 12/12-h light–dark cycle. Rectal temperature was measured every 15 min from 4:00 a.m. to 9:30 a.m. and from 4:00 p.m. to 9:30 p.m., following subcutaneous injection of each compound at either 5:00 a.m. or 5:00 p.m. MLT (40 mg/kg) had no effect when injected at 5 a.m., whereas it decreased Tb during the light phase only when injected at 5:00 p.m. This effect was blocked by the selective MT2 receptor antagonist 4P-PDOT and the non-selective MT1/MT2 receptor antagonist, luzindole, but not by the α1/MT3 receptors antagonist prazosin. However, unlike MLT, neither the selective MT1 receptor partial agonist UCM871 (14 mg/kg) nor the selective MT2 partial agonist UCM924 (40 mg/kg) altered Tb during the light phase. In contrast, UCM871 injected at 5:00 p.m. increased Tb at the beginning of the dark phase, whereas UCM924 injected at 5:00 a.m. decreased Tb at the end of the dark phase. These effects were blocked by luzindole and 4P-PDOT, respectively. The MT3 receptor agonist GR135531 (10 mg/kg) did not affect Tb. These data suggest that the simultaneous activation of both MT1 and MT2 receptors is necessary to regulate Tb during the light phase, whereas in a complex but yet unknown manner, they regulate Tb differently during the dark phase. Overall, MT1 and MT2 receptors display complementary but also distinct roles in modulating circadian fluctuations of Tb.

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