Thursday, July 28, 2016

Synthesis of New Thiazolo[4,5-d]pyrimidines as Corticotropin Releasing Factor Modulators

Author(s):

Bhimanna Kuppast, Katerina Spyridaki, Christophina Lynch, Yueshan Hu, George Liapakis, Gareth E. Davies and Hesham FahmyPages 50-59 (10)

Abstract:


Corticotropin-releasing factor (CRF) is a neurohormone that plays a crucial role in integrating the body’s overall response to stress. It appears necessary and sufficient for the organism to mount functional, physiological and endocrine responses to stressors. CRF is released in response to various triggers such as chronic stress. The role of CRF and its involvement in these neurological disorders suggest that new drugs that can target the CRF function or bind to its receptors may represent a new development of neuropsychiatric medicines to treat various stress-related disorders including depression, anxiety and addictive disorders. Based on pharmacophore of the CRF1 receptor antagonists, a new series of thiazolo[4,5-d] pyrimidines were synthesized as Corticotropin-releasing factor (CRF) receptor modulators and the prepared compounds carry groups shown to produce optimum binding affinity to CRF receptors. Twenty two compounds were evaluated for their CRF1 receptor binding affinity in HEK 293 cell lines and two compounds 5o and 5s showed approximately 25% binding affinity to CRF1 receptors. Selected compounds (5c and 5f) were also evaluated for their effect on expression of genes associated with depression and anxiety disorders such as CRF1, CREB1, MAO-A, SERT, NPY, DatSLC6a3, and DBH and significant upregulation of CRF1 mRNA has been observed with compound 5c.

Keywords:

Thiazolo[4, 5-d]pyrimidines, corticotropin releasing factor, antalarmin, anxiety, depression.

Affiliation:

Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.

Graphical Abstract:



Read Full-Text article

Overview of Binding Free Energy Calculation Techniques for Elucidation of Biological Processes and for Drug Discovery

Author(s):

Takeshi Ashida and Takeshi KikuchiPages 248-253 (6)

Abstract:


The elucidation of the interactions between a protein and a ligand or proteins is a key issue for understanding of functional processes of various proteins, enzymes and receptors in biological organisms, system biology and drug design. One of the most important matters in these problems is the accurate estimation of binding free energy between a protein and a ligand or proteins. In the present review, we overview various techniques and introduce a new technique for estimation of binding free energy calculations. We also discuss possible ways to incorporate the effect of fect of solvent.

Keywords:

Binding free energy, Drug design, Biological processes, Free energy variational principle, Molecular dynamics simulations, Solvent model.

Affiliation:

Department of Bioinformatics, College of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan.

Graphical Abstract:



Read Full-Text article

    Practical Application of Antidiabetic Efficacy of Lycium barbarum Polysaccharide in Patients with Type 2 Diabetes

    Author(s):

    Huizhen Cai, Fukang Liu, Pingguo Zuo, Guiling Huang, Zhixiu Song, Tingting Wang, Huixia Lu, Fei Guo, Chao Han and Guiju SunPages 383-390 (8)

    Abstract:


    Lycium barbarum polysaccharide (LBP) has traditionally been used in Chinese medicine as a chief ingredient of Lycium barbarum(wolf berry/goji berry) for the treatment of various diseases with the symptoms of frequent drinking and urination. This study was conducted as a randomized, controlled clinical trial. A total of 67 patients with type 2 diabetes (30 in control group and 37 in LBP group) were enrolled in this prospective, randomized, double-blind study (administration at 300mg/day body weight). In order to observe the hypoglycemic and lipid-lowering activity of LBP in patients with type 2 diabetes after dinner, various tests were conducted between control and LBP intervention groups in 3 months. Although, the study had small sample size and short follow-up, significant findings were observed. The results of our study indicated a remarkable protective effect of LBP in patients with type 2 diabetes. Serum glucose was found to be significantly decreased and insulinogenic index increased during OMTT after 3 months administration of LBP. LBP also increased HDL levels in patients with type 2 diabetes. It showed more obvious hypoglycemic efficacy for those people who did not take any hypoglycemic medicine compared to patients taking hypoglycemic medicines. This study showed LBP to be a good potential treatment aided-agent for type 2 diabetes.

    Keywords:

    Lycium barbarum polysaccharide, type 2 diabetes, glucose, lipids, cytokines.

    Affiliation:

    Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Dingjia Qiao 87, Nanjing 210009, P.R. China.

    Graphical Abstract:



    Read Full-Text article

    Long Term Stability Evaluation of Prostacyclin Released from Biomedical Device through Turbiscan Lab Expert

    Author(s):

    Christian Celia, Marcello Locatelli, Felisa Cilurzo, Donato Cosco, Emanuela Gentile, Daniela Scalise, Maria Carafa, Cinzia Anna Ventura, Mathias Fleury, Christelle Tisserand, Renato. C Barbacane, Massimo Fresta, Luisa Di Marzio and Donatella PaolinoPages 391-399 (9)

    Abstract:


    Therapeutic guidelines indicate prostacyclin as the first line of treatment in inflammation and vascular diseases. Prostacyclins prevent formation of the platelet plug involved in primary hemostasis by inhibiting platelet activation and, combined with thromboxane, are effective vasodilators in vascular damage.
    Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease II guidelines indicates prostacyclins; in particular, Iloprost, as the first therapeutic option for treating peripheral arterial disease. However, therapeutic efficacy of Iloprost has witnessed several drawbacks that have occurred in patients receiving repeated weekly administration of the drug by intravenous infusions. Adverse reactions arose under perfusion with Iloprost for 6 h and patient compliance was drastically decreased. Biomedical devices could provide a suitable alternative to overcome these drawbacks. In particular, elastomeric pumps, filled with Iloprost isotonic solution, could slowly release the drug, thus decreasing its side effects, representing a valid alternative to hospitalization of patients affected by peripheral arterial disease. However, the home therapy treatment of patients requires long-term stability of Iloprost in solution-loaded elastomeric pumps.
    The aim of this work was to investigate the long-term stability of Iloprost isotonic solution in biomedical devices using Turbiscan technology. Turbiscan Lab Expert (L’Union, France) predicts the long-term stability of suspensions, emulsions and colloidal formulations by measuring backscattering and transmission of particulates dispersed in solution. The formulations were evaluated by measuring the variation of physical-chemical properties of colloids and suspensions as a function of backscattering and transmission modifications. In addition, the release profile of Iloprost isotonic solution from the biomedical device was evaluated.

    Keywords:

    Critical limb ischemia, disposable infusion pumps, endoprost, high performance liquid chromatography, prostacyclin, Turbiscan technology.

    Affiliation:

    Department of Pharmacy, University “G. d'Annunzio” of Chieti - Pescara, Via dei Vestini 31, 66100 Chieti, Italy

    Graphical Abstract:



    Read Full-Text article