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Pharmaceuticals, Volume 6, Issue 4 (April 2013), Pages 440-578

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Research

Jump to: Review

Open AccessArticle Interactions of a Dopamine D1 Receptor Agonist with Glutamate NMDA Receptor Antagonists on the Volitional Consumption of Ethanol by the mHEP Rat
Pharmaceuticals 2013, 6(4), 469-479; doi:10.3390/ph6040469
Received: 25 December 2012 / Revised: 23 February 2013 / Accepted: 15 March 2013 / Published: 26 March 2013
Cited by 1 | PDF Full-text (212 KB) | HTML Full-text | XML Full-text
Abstract
Stimulation of the dopamine D1 receptor is reported to cause the phosphorylation of DARPP-32 at the thre34 position and activates the protein. If intracellular Ca2+ is increased, such as after activation of the glutamate NMDA receptor, calcineurin activity increases and the phosphates
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Stimulation of the dopamine D1 receptor is reported to cause the phosphorylation of DARPP-32 at the thre34 position and activates the protein. If intracellular Ca2+ is increased, such as after activation of the glutamate NMDA receptor, calcineurin activity increases and the phosphates will be removed. This balance of phosphorylation control suggests that a D1 receptor agonist and a NMDA glutamate receptor antagonist should have additive or synergistic actions to increase activated DARPP-32 and consequent behavioral effects. This hypothesis was tested in a volitional consumption of ethanol model: the selectively bred Myers’ high ethanol preferring (mHEP) rat. A 3-day baseline period was followed by 3-days of twice daily injections of drug(s) or vehicle(s) and then a 3-day post-treatment period. Vehicle, the D1 agonist SKF 38393, the non-competitive NMDA receptor antagonist memantine, or their combination were injected 2 h before and after lights out. The combination of 5.0 mg/kg SKF 38393 with either 3.0 or 10 mg/kg memantine did not produce an additive or synergistic effect. For example, 5.0 mg/kg SKF reduced consumption of ethanol by 27.3% and 10 mg/kg memantine by 39.8%. When combined, consumption declined by 48.2% and the proportion of ethanol solution to total fluids consumed declined by 17%. However, the consumption of food also declined by 36.6%. The latter result indicates that this dose combination had a non-specific effect. The combination of SKF 38393 with (+)-MK-801, another NMDA receptor antagonist, also failed to show an additive effect. The lack of additivity and specificity suggests that the hypothesis may not be correct for this in vivo model.  The interaction of these different receptor systems with intraneuronal signaling and behaviors needs to be studied further. Full article
(This article belongs to the Special Issue NMDA Receptor Antagonists for Treatment of CNS Disorders)
Open AccessArticle The Three Catecholics Benserazide, Catechol and Pyrogallol are GPR35 Agonists
Pharmaceuticals 2013, 6(4), 500-509; doi:10.3390/ph6040500
Received: 6 March 2013 / Revised: 20 March 2013 / Accepted: 1 April 2013 / Published: 8 April 2013
Cited by 4 | PDF Full-text (939 KB) | HTML Full-text | XML Full-text
Abstract Nearly 1% of all clinically used drugs are catecholics, a family of catechol-containing compounds. Using label-free dynamic mass redistribution and Tango β-arrestin translocation assays, we show that several catecholics, including benserazide, catechol, 3-methoxycatechol, pyrogallol, (+)-taxifolin and fenoldopam, display agonistic activity against GPR35. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessArticle Toxicity Studies on Novel N-Substituted Bicyclo-Heptan-2-Amines at NMDA Receptors
Pharmaceuticals 2013, 6(4), 536-545; doi:10.3390/ph6040536
Received: 25 January 2013 / Revised: 9 April 2013 / Accepted: 9 April 2013 / Published: 12 April 2013
Cited by 3 | PDF Full-text (1046 KB) | HTML Full-text | XML Full-text
Abstract
Several novel norcamphor derivatives were designed and synthesized as uncompetitive NMDA receptor antagonists at the phencyclidine (PCP) binding site. Such compounds have potential as ligands for understanding and possibly the treatment of several neurodegenerative disorders and other glutamate-dependent disorders. We examined the toxic
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Several novel norcamphor derivatives were designed and synthesized as uncompetitive NMDA receptor antagonists at the phencyclidine (PCP) binding site. Such compounds have potential as ligands for understanding and possibly the treatment of several neurodegenerative disorders and other glutamate-dependent disorders. We examined the toxic effects of the compounds as compared with memantine, an NMDA receptor antagonist that is FDA approved for treatment of Alzheimer’s disease, by testing these compounds on two cell lines: MDCK (to mimic blood brain barrier) and N2a (a neuronal cell line). The compounds showed toxicity profiles similar to those of memantine i.e., dose dependence above 100 μM and IC50 values above 150 μM for each cell line. It is known that the serum level of memantine under therapeutic conditions in patients is about 1 µM, indicting these compounds could have acceptable therapeutic indexes. 2-Phenyl-N-(2-(piperidin-1-yl) ethyl)bicyclo[2.2.1]heptan-2-amine (5a) was found to possess acceptable toxicity profiles in both cell lines. Interestingly, this was the compound identified as a good lead in our previous studies based on binding and anticonvulsant (MES) activity studies. It has thus emerged as an excellent lead compound for further studies. Full article
(This article belongs to the Special Issue NMDA Receptor Antagonists for Treatment of CNS Disorders)
Figures

Open AccessCommunication An Allosteric Modulator of the Adenosine A1 Receptor Improves Cardiac Function Following Ischaemia in Murine Isolated Hearts
Pharmaceuticals 2013, 6(4), 546-556; doi:10.3390/ph6040546
Received: 4 March 2013 / Revised: 26 March 2013 / Accepted: 1 April 2013 / Published: 12 April 2013
Cited by 5 | PDF Full-text (517 KB) | HTML Full-text | XML Full-text
Abstract
The effect of an allosteric modulator of the adenosine A1 receptors was investigated using an ischaemia-reperfusion protocol in murine isolated hearts. Isolated hearts were perfused with Kreb-Henseleit solution gassed with carbogen gas (95% O2 and 5% CO2) in Langendorff
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The effect of an allosteric modulator of the adenosine A1 receptors was investigated using an ischaemia-reperfusion protocol in murine isolated hearts. Isolated hearts were perfused with Kreb-Henseleit solution gassed with carbogen gas (95% O2 and 5% CO2) in Langendorff mode and electrically paced at 480 bpm. Following 20 min equilibration and 20 min global normothermic ischaemia, the allosteric modulator VCP333 (1 μM) or the adenosine A1 receptor partial agonist VCP102 (10 μM) were infused after 5 min of reperfusion for 15 min. Upon termination of the drug treatment, reperfusion continued for a further 40 min. At the end of 60 min reperfusion, treatment with VCP333 or VCP102 improved the recovery of the left ventricular developed pressure when compared to control group responses (p < 0.05). Neither compound affected end diastolic pressure, coronary flow rates or dP/dtmax values when compared to control tissues during reperfusion (p > 0.05). The infusion of VCP102 or VCP333 during reperfusion reduced cardiac troponin I efflux to 6.7% and 25% respectively of control heart efflux (p < 0.05). This data indicates that the allosteric modulator of the adenosine A1 receptor (VCP333) has similar characteristics to the adenosine receptor partial agonist VCP102 as it improves cardiac function and reduces myocardial cell death following an ischaemic episode. Full article
(This article belongs to the Special Issue Purine and Its Derivatives)

Review

Jump to: Research

Open AccessReview Design of siRNA Therapeutics from the Molecular Scale
Pharmaceuticals 2013, 6(4), 440-468; doi:10.3390/ph6040440
Received: 24 January 2013 / Revised: 27 February 2013 / Accepted: 13 March 2013 / Published: 25 March 2013
Cited by 11 | PDF Full-text (679 KB) | HTML Full-text | XML Full-text
Abstract
While protein-based therapeutics is well-established in the market, development of nucleic acid therapeutics has lagged. Short interfering RNAs (siRNAs) represent an exciting new direction for the pharmaceutical industry. These small, chemically synthesized RNAs can knock down the expression of target genes through the
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While protein-based therapeutics is well-established in the market, development of nucleic acid therapeutics has lagged. Short interfering RNAs (siRNAs) represent an exciting new direction for the pharmaceutical industry. These small, chemically synthesized RNAs can knock down the expression of target genes through the use of a native eukaryotic pathway called RNA interference (RNAi). Though siRNAs are routinely used in research studies of eukaryotic biological processes, transitioning the technology to the clinic has proven challenging. Early efforts to design an siRNA therapeutic have demonstrated the difficulties in generating a highly-active siRNA with good specificity and a delivery vehicle that can protect the siRNA as it is transported to a specific tissue. In this review article, we discuss design considerations for siRNA therapeutics, identifying criteria for choosing therapeutic targets, producing highly-active siRNA sequences, and designing an optimized delivery vehicle. Taken together, these design considerations provide logical guidelines for generating novel siRNA therapeutics. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Open AccessReview NMDA Receptor Antagonists for Treatment of Depression
Pharmaceuticals 2013, 6(4), 480-499; doi:10.3390/ph6040480
Received: 31 January 2013 / Revised: 27 March 2013 / Accepted: 27 March 2013 / Published: 3 April 2013
Cited by 6 | PDF Full-text (237 KB) | HTML Full-text | XML Full-text
Abstract
Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However,
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Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA) receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker), and CGP 37849 (an NMDA receptor antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery. Full article
(This article belongs to the Special Issue NMDA Receptor Antagonists for Treatment of CNS Disorders)
Open AccessReview Delivery of RNAi-Based Oligonucleotides by Electropermeabilization
Pharmaceuticals 2013, 6(4), 510-521; doi:10.3390/ph6040510
Received: 31 December 2012 / Revised: 19 March 2013 / Accepted: 27 March 2013 / Published: 10 April 2013
PDF Full-text (622 KB) | HTML Full-text | XML Full-text
Abstract
For more than a decade, understanding of RNA interference (RNAi) has been a growing field of interest. The potent gene silencing ability that small oligonucleotides have offers new perspectives for cancer therapeutics. One of the present limits is that many biological barriers exist
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For more than a decade, understanding of RNA interference (RNAi) has been a growing field of interest. The potent gene silencing ability that small oligonucleotides have offers new perspectives for cancer therapeutics. One of the present limits is that many biological barriers exist for their efficient delivery into target cells or tissues. Electropermeabilization (EP) is one of the physical methods successfully used to transfer small oligonucleotides into cells or tissues. EP consists in the direct application of calibrated electric pulses to cells or tissues that transiently permeabilize the plasma membranes, allowing efficient in vitro and in vivo. cytoplasmic delivery of exogenous molecules. The present review reports on the type of therapeutic RNAi-based oligonucleotides that can be electrotransferred, the mechanism(s) of their electrotransfer and the technical settings for pre-clinical purposes. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Open AccessReview Disease-Causing Allele-Specific Silencing by RNA Interference
Pharmaceuticals 2013, 6(4), 522-535; doi:10.3390/ph6040522
Received: 27 December 2012 / Revised: 28 March 2013 / Accepted: 2 April 2013 / Published: 11 April 2013
Cited by 6 | PDF Full-text (270 KB) | HTML Full-text | XML Full-text
Abstract
Small double-stranded RNAs (dsRNAs) of approximately 21-nucleotides in size, referred to as small interfering RNA (siRNA) duplexes, can induce sequence-specific posttranscriptional gene silencing, or RNA interference (RNAi). Since chemically synthesized siRNA duplexes were found to induce RNAi in mammalian cells, RNAi has become
[...] Read more.
Small double-stranded RNAs (dsRNAs) of approximately 21-nucleotides in size, referred to as small interfering RNA (siRNA) duplexes, can induce sequence-specific posttranscriptional gene silencing, or RNA interference (RNAi). Since chemically synthesized siRNA duplexes were found to induce RNAi in mammalian cells, RNAi has become a powerful reverse genetic tool for suppressing the expression of a gene of interest in mammals, including human, and its application has been expanding to various fields. Recent studies further suggest that synthetic siRNA duplexes have the potential for specifically inhibiting the expression of an allele of interest without suppressing the expression of other alleles, i.e., siRNA duplexes likely confer allele-specific silencing. Such gene silencing by RNAi is an advanced technique with very promising applications. In this review, I would like to discuss the potential utility of allele-specific silencing by RNAi as a therapeutic method for dominantly inherited diseases, and describe possible improvements in siRNA duplexes for enhancing their efficacy. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Open AccessReview Biologics in Dermatology
Pharmaceuticals 2013, 6(4), 557-578; doi:10.3390/ph6040557
Received: 31 January 2013 / Revised: 26 February 2013 / Accepted: 7 April 2013 / Published: 17 April 2013
Cited by 5 | PDF Full-text (485 KB) | HTML Full-text | XML Full-text
Abstract
Skin and subcutaneous diseases affect millions of people worldwide, causing significant morbidity. Biologics are becoming increasingly useful for the treatment of many skin diseases, particularly as alternatives for patients who have failed to tolerate or respond to conventional systemic therapies. Biological therapies provide
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Skin and subcutaneous diseases affect millions of people worldwide, causing significant morbidity. Biologics are becoming increasingly useful for the treatment of many skin diseases, particularly as alternatives for patients who have failed to tolerate or respond to conventional systemic therapies. Biological therapies provide a targeted approach to treatment through interaction with specific components of the underlying immune and inflammatory disease processes. This review article examines the increasing evidence base for biologics in dermatology, including well-established treatments and novel agents. Full article
(This article belongs to the Special Issue Biologics)

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