From Receptor Selectivity to Functional Selectivity: The Rise of Biased Agonism in 5-HT1A Receptor Drug Discovery

2019 ◽  
Vol 19 (26) ◽  
pp. 2393-2420 ◽  
Author(s):  
Joanna Sniecikowska ◽  
Adrian Newman-Tancredi ◽  
Marcin Kolaczkowski
Keyword(s):  
Drug Discovery ◽  
Therapeutic Potential ◽  
Receptor Activation ◽  
Brain Regions ◽  
Molecular Signaling ◽  
Active Metabolites ◽  
Innovative Drug ◽  
Biased Agonism

: Despite extensive efforts to design serotonin 5-HT1A receptor compounds, there are currently no clinically available selective agonists to explore the therapeutic potential of activating this receptor. Commonly used drugs targeting 5-HT1A receptors, such as buspirone or other azapirone compounds, possess only limited selectivity over cross-reacting sites, act as partial agonists for 5-HT1A receptor activation, and are metabolically labile, generating active metabolites. In addition, drug discovery has been hampered by the multiplicity of 5-HT1A receptor subpopulations, expressed in different brain regions, that are coupled to distinct molecular signaling mechanisms and mediate a wide variety of physiological responses, both desired and undesired. : In this context, advances in 5-HT1A receptor drug discovery have attracted attention of novel ‘biased agonists’ that are selective, efficacious and preferentially target the brain regions that mediate therapeutic activity without triggering side effects. The prototypical first-in-class compound NLX-101 (a.k.a. F15599; 3-chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin- 1-yl]methanone), preferentially activates 5-HT1A receptors in cortical regions and exhibits potent, rapidacting and sustained antidepressant-like and procognitive properties in animal models. : Here the background has been reviewed that led to the discovery of the class of 1-(1-benzoylpiperidin-4- yl)methanamine derivatives, including NLX-101, as well as recent advances in discovery of novel 5-HT1A receptor biased agonists, notably aryloxyethyl derivatives of 1‑(1-benzoylpiperidin-4yl)methanamine which show promising pharmacological activity both in vitro and in vivo. : Overall, the results suggest that opportunities exist for innovative drug discovery of selective 5-HT1A receptor biased agonists that may open new avenues for the treatment of CNS disorders involving dysfunction of serotonergic neurotransmission.

Physiology, Pharmacology, and Topography of Cholinergic Neocortical Oscillations In Vitro

1997 ◽  
Vol 77 (5) ◽  
pp. 2427-2445 ◽  
Author(s):  
Heath S. Lukatch ◽  
M. Bruce Maciver
Keyword(s):  
Current Source ◽  
Brain Slices ◽  
Receptor Activation ◽  
Brain Regions ◽  
Oscillatory Activity ◽  
Cortical Layers ◽  
Eeg Activity ◽  
Layer 2

Lukatch, Heath S. and M. Bruce MacIver. Physiology, pharmacology, and topography of cholinergic neocortical oscillations in vitro. J. Neurophysiol. 77: 2427–2445, 1997. Rat neocortical brain slices generated rhythmic extracellular field [microelectroencephalogram (micro-EEG)] oscillations at theta frequencies (3–12 Hz) when exposed to pharmacological conditions that mimicked endogenous ascending cholinergic and GABAergic inputs. Use of the specific receptor agonist and antagonist carbachol and bicuculline revealed that simultaneous muscarinic receptor activation and γ-aminobutyric acid-A (GABAA)-mediated disinhibition werenecessary to elicit neocortical oscillations. Rhythmic activity was independent of GABAB receptor activation, but required intact glutamatergic transmission, evidenced by blockade or disruption of oscillations by 6-cyano-7-nitroquinoxaline-2,3-dione and (±)-2-amino-5-phosphonovaleric acid, respectively. Multisite mapping studies showed that oscillations were localized to areas 29d and 18b (Oc2MM) and parts of areas 18a and 17. Peak oscillation amplitudes occurred in layer 2/3, and phase reversals were observed in layers 1 and 5. Current source density analysis revealed large-amplitude current sinks and sources in layers 2/3 and 5, respectively. An initial shift in peak inward current density from layer 1 to layer 2/3 indicated that two processes underlie an initial depolarization followed by oscillatory activity. Laminar transections localized oscillation-generating circuitry to superficial cortical layers and sharp-spike-generating circuitry to deep cortical layers. Whole cell recordings identified three distinct cell types based on response properties during rhythmic micro-EEG activity: oscillation-on (theta-on) and -off (theta-off) neurons, and transiently depolarizing glial cells. Theta-on neurons displayed membrane potential oscillations that increased in amplitude with hyperpolarization (from −30 to −90 mV). This, taken together with a glutamate antagonist-induced depression of rhythmic micro-EEG activity, indicated that cholinergically driven neocortical oscillations require excitatory synaptic transmission. We conclude that under the appropriate pharmacological conditions, neocortical brain slices were capable of producing localized theta frequency oscillations. Experiments examining oscillation physiology, pharmacology, and topography demonstrated that neocortical brain slice oscillations share many similarities with the in vivo and in vitro theta EEG activity recorded in other brain regions.

scholarly journals Anti-EphA2 Antibodies with Distinct In Vitro Properties Have Equal In Vivo Efficacy in Pancreatic Cancer

2009 ◽  
Vol 2009 ◽  
pp. 1-10 ◽  
Author(s):  
Helenia Ansuini ◽  
Annalisa Meola ◽  
Zeynep Gunes ◽  
Valentina Paradisi ◽  
Monica Pezzanera ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Monoclonal Antibodies ◽  
Therapeutic Potential ◽  
Tumor Cell Line ◽  
Immunohistochemical Analysis ◽  
Receptor Activation ◽  
Rapid Identification ◽  
Antibody Treatment

The EphA2 receptor tyrosine kinase is overexpressed in a variety of human epithelial cancers and is a determinant of malignant cellular behavior in pancreatic adenocarcinoma cells. Moreover, it is expressed in tumor endothelium and its activation promotes angiogenesis. To better clarify the therapeutic potential of monoclonal antibodies (mAbs) directed to the EphA2 receptor, we generated a large number of mAbs by differential screening of phage-Ab libraries by oligonucleotide microarray technology and implemented a strategy for the rapid identification of antibodies with the desired properties. We selected two high-affinity and highly specific EphA2 monoclonal antibodies with different in vitro properties on the human pancreatic tumor cell line MiaPaCa2. One is a potent EphA2-agonistic antibody, IgG25, that promotes receptor endocytosis and subsequent degradation, and the second is a ligand antagonist, IgG28, that blocks the binding to ephrin A1 and is cross-reactive with the mouse EphA2 receptor. We measured the effect of antibody treatment on the growth of MiaPaCa2 cells orthotopically transplanted in nude mice. Both IgG25 and IgG28 had strong antitumor and antimetastatic efficacy. In vivo treatment with IgG25 determined the reduction of the EphA2 protein levels in the tumor and the phosphorylation of FAK on Tyr576 while administration of IgG28 caused a decrease in tumor vascularization as measured by immunohistochemical analysis of CD31 in tumor sections. These data show that in a pancreatic cancer model comparable therapeutic efficacy is obtained either by promoting receptor degradation or by blocking receptor activation.

scholarly journals Target-Based Small Molecule Drug Discovery Towards Novel Therapeutics for Inflammatory Bowel Diseases

2021 ◽  
Vol 27 (Supplement_2) ◽  
pp. S38-S62 ◽  
Author(s):  
Yi Li ◽  
Jianping Chen ◽  
Andrew A Bolinger ◽  
Haiying Chen ◽  
Zhiqing Liu ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Therapeutic Potential ◽  
Biological Response ◽  
Mucosal Inflammation ◽  
Interacting Protein ◽  
Iκb Kinase ◽  
Tnf Α ◽  
Inflammatory Bowel

Abstract Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a class of severe and chronic diseases of the gastrointestinal (GI) tract with recurrent symptoms and significant morbidity. Long-term persistence of chronic inflammation in IBD is a major contributing factor to neoplastic transformation and the development of colitis-associated colorectal cancer. Conversely, persistence of transmural inflammation in CD is associated with formation of fibrosing strictures, resulting in substantial morbidity. The recent introduction of biological response modifiers as IBD therapies, such as antibodies neutralizing tumor necrosis factor (TNF)-α, have replaced nonselective anti-inflammatory corticosteroids in disease management. However, a large proportion (~40%) of patients with the treatment of anti-TNF-α antibodies are discontinued or withdrawn from therapy because of (1) primary nonresponse, (2) secondary loss of response, (3) opportunistic infection, or (4) onset of cancer. Therefore, the development of novel and effective therapeutics targeting specific signaling pathways in the pathogenesis of IBD is urgently needed. In this comprehensive review, we summarize the recent advances in drug discovery of new small molecules in preclinical or clinical development for treating IBD that target biologically relevant pathways in mucosal inflammation. These include intracellular enzymes (Janus kinases, receptor interacting protein, phosphodiesterase 4, IκB kinase), integrins, G protein-coupled receptors (S1P, CCR9, CXCR4, CB2) and inflammasome mediators (NLRP3), etc. We will also discuss emerging evidence of a distinct mechanism of action, bromodomain-containing protein 4, an epigenetic regulator of pathways involved in the activation, communication, and trafficking of immune cells. We highlight their chemotypes, mode of actions, structure-activity relationships, characterizations, and their in vitro/in vivo activities and therapeutic potential. The perspectives on the relevant challenges, new opportunities, and future directions in this field are also discussed.

scholarly journals Potential Therapeutic Targets of Quercetin, a Plant Flavonol, and Its Role in the Therapy of Various Types of Cancer through the Modulation of Various Cell Signaling Pathways

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1315
Author(s):  
Saleh A. Almatroodi ◽  
Mohammed A. Alsahli ◽  
Ahmad Almatroudi ◽  
Amit Kumar Verma ◽  
Abdulaziz Aloliqi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Cancer Biology ◽  
Therapeutic Potential ◽  
Phosphatidyl Inositol ◽  
Mitogen Activated Protein Kinase ◽  
Molecular Signaling ◽  
Anticancer Properties

Polyphenolic flavonoids are considered natural, non-toxic chemopreventers, which are most commonly derived from plants, fruits, and vegetables. Most of these polyphenolics exhibit remarkable antioxidant, anti-inflammatory, and anticancer properties. Quercetin (Qu) is a chief representative of these polyphenolic compounds, which exhibits excellent antioxidant and anticancer potential, and has attracted the attention of researchers working in the area of cancer biology. Qu can regulate numerous tumor-related activities, such as oxidative stress, angiogenesis, cell cycle, tumor necrosis factor, proliferation, apoptosis, and metastasis. The anticancer properties of Qu mainly occur through the modulation of vascular endothelial growth factor (VEGF), apoptosis, phosphatidyl inositol-3-kinase (P13K)/Akt (proteinase-kinase B)/mTOR (mammalian target of rapamycin), MAPK (mitogen activated protein kinase)/ERK1/2 (extracellular signal-regulated kinase 1/2), and Wnt/β-catenin signaling pathways. The anticancer potential of Qu is documented in numerous in vivo and in vitro studies, involving several animal models and cell lines. Remarkably, this phytochemical possesses toxic activities against cancerous cells only, with limited toxic effects on normal cells. In this review, we present extensive research investigations aimed to discuss the therapeutic potential of Qu in the management of different types of cancers. The anticancer potential of Qu is specifically discussed by focusing its ability to target specific molecular signaling, such as p53, epidermal growth factor receptor (EGFR), VEGF, signal transducer and activator of transcription (STAT), PI3K/Akt, and nuclear factor kappa B (NF-κB) pathways. The anticancer potential of Qu has gained remarkable interest, but the exact mechanism of its action remains unclear. However, this natural compound has great pharmacological potential; it is now believed to be a complementary—or alternative—medicine for the prevention and treatment of different cancers.

scholarly journals Curcumin, a Multifaceted Hormetic Agent, Mediates an Intricate Crosstalk between Mitochondrial Turnover, Autophagy, and Apoptosis

2020 ◽  
Vol 2020 ◽  
pp. 1-23 ◽  
Author(s):  
Nathan Earl Rainey ◽  
Aoula Moustapha ◽  
Patrice Xavier Petit
Keyword(s):  
Cell Death ◽  
Calcium Release ◽  
Therapeutic Potential ◽  
Molecular Signaling ◽  
M Cell ◽  
Cycle Arrest ◽  
Acute Responses ◽  
High Doses

Curcumin has extensive therapeutic potential because of its antioxidant, anti-inflammatory, and antiproliferative properties. Multiple preclinical studies in vitro and in vivo have proven curcumin to be effective against various cancers. These potent effects are driven by curcumin’s ability to induce G2/M cell cycle arrest, induce autophagy, activate apoptosis, disrupt molecular signaling, inhibit invasion and metastasis, and increase the efficacy of current chemotherapeutics. Here, we focus on the hormetic behavior of curcumin. Frequently, low doses of natural chemical products activate an adaptive stress response, whereas high doses activate acute responses like autophagy and cell death. This phenomenon is often referred to as hormesis. Curcumin causes cell death and primarily initiates an autophagic step (mitophagy). At higher doses, cells undergo mitochondrial destabilization due to calcium release from the endoplasmic reticulum, and die. Herein, we address the complex crosstalk that involves mitochondrial biogenesis, mitochondrial destabilization accompanied by mitophagy, and cell death.

scholarly journals Therapeutic Potential of Curcumin for the Treatment of Brain Tumors

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Neil V. Klinger ◽  
Sandeep Mittal
Keyword(s):  
Brain Tumors ◽  
Therapeutic Potential ◽  
Standard Of Care ◽  
Molecular Signaling ◽  
M Cell ◽  
Cycle Arrest ◽  
Low Toxicity ◽  
Apoptotic Pathways

Brain malignancies currently carry a poor prognosis despite the current multimodal standard of care that includes surgical resection and adjuvant chemotherapy and radiation. As new therapies are desperately needed, naturally occurring chemical compounds have been studied for their potential chemotherapeutic benefits and low toxicity profile. Curcumin, found in the rhizome of turmeric, has extensive therapeutic promise via its antioxidant, anti-inflammatory, and antiproliferative properties. Preclinicalin vitroandin vivodata have shown it to be an effective treatment for brain tumors including glioblastoma multiforme. These effects are potentiated by curcumin’s ability to induce G2/M cell cycle arrest, activation of apoptotic pathways, induction of autophagy, disruption of molecular signaling, inhibition of invasion, and metastasis and by increasing the efficacy of existing chemotherapeutics. Further, clinical data suggest that it has low toxicity in humans even at large doses. Curcumin is a promising nutraceutical compound that should be evaluated in clinical trials for the treatment of human brain tumors.

scholarly journals Human cerebral organoids establish subcortical projections in the mouse brain after transplantation

2020 ◽  
Author(s):  
Xin Dong ◽  
Shi-Bo Xu ◽  
Xin Chen ◽  
Mengdan Tao ◽  
Xiao-Yan Tang ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Therapeutic Potential ◽  
Neurological Diseases ◽  
Brain Regions ◽  
Synaptic Connections ◽  
Glutamatergic Neurons ◽  
Human Brain Development ◽  
Basal Brain

Abstract Numerous studies have used human pluripotent stem cell-derived cerebral organoids to elucidate the mystery of human brain development and model neurological diseases in vitro, but the potential for grafted organoid-based therapy in vivo remains unknown. Here, we optimized a culturing protocol capable of efficiently generating small human cerebral organoids. After transplantation into the mouse medial prefrontal cortex, the grafted human cerebral organoids survived and extended projections over 4.5 mm in length to basal brain regions within 1 month. The transplanted cerebral organoids generated human glutamatergic neurons that acquired electrophysiological maturity in the mouse brain. Importantly, the grafted human cerebral organoids functionally integrated into pre-existing neural circuits by forming bidirectional synaptic connections with the mouse host neurons. Furthermore, compared to control mice, the mice transplanted with cerebral organoids showed an increase in freezing time in response to auditory conditioned stimuli, suggesting the potentiation of the startle fear response. Our study showed that subcortical projections can be established by microtransplantation and may provide crucial insights into the therapeutic potential of human cerebral organoids for neurological diseases.

The effects of polydeoxyribonucleotide on wound healing and tissue regeneration: a systematic review of the literature

2020 ◽  
Vol 15 (6) ◽  
pp. 1801-1821
Author(s):  
Maria T Colangelo ◽  
Carlo Galli ◽  
Stefano Guizzardi
Keyword(s):  
Wound Healing ◽  
Tissue Regeneration ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Receptor Activation ◽  
Cochrane Central Register ◽  
Eligibility Criteria ◽  
Study Results

Aim: The present study evaluated the effects of polydeoxyribonucleotide (PDRN) on tissue regeneration, paying special attention to the molecular mechanisms that underlie its tissue remodeling actions to better identify its effective therapeutic potential in wound healing. Materials & methods: Strategic searches were conducted through MEDLINE/PubMed, Google Scholar, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials, from their earliest available dates to March 2020. The studies were included with the following eligibility criteria: studies evaluating tissue regeneration, and being an in vitro, in vivo and clinical study. Results: Out of more than 90 articles, 34 fulfilled the eligibility criteria. All data obtained proved the ability of PDRN in promoting a physiological tissue repair through salvage pathway and adenosine A2A receptor activation. Conclusion: Up to date PDRN has proved promising results in term of wound regeneration, healing time and absence of side effects.

scholarly journals Therapeutic Potential of Plants as Anti-Microbials for Drug Discovery

2010 ◽  
Vol 7 (3) ◽  
pp. 283-294 ◽  
Author(s):  
Ramar Perumal Samy ◽  
Ponnampalam Gopalakrishnakone
Keyword(s):  
Drug Discovery ◽  
Therapeutic Potential ◽  
Modern Medicine ◽  
Current Status ◽  
Traditional Medicinal Plants ◽  
Recent Trends ◽  
Clinical Trails ◽  
Treatment Of Infection

The uses of traditional medicinal plants for primary health care have steadily increased worldwide in recent years. Scientists are in search of new phytochemicals that could be developed as useful anti-microbials for treatment of infectious diseases. Currently, out of 80% of pharmaceuticals derived from plants, very few are now being used as anti-microbials. Plants are rich in a wide variety of secondary metabolites that have found anti-microbial properties. This review highlights the current status of traditional medicine, its contribution to modern medicine, recent trends in the evaluation of anti-microbials with a special emphasis upon some tribal medicine,in vitroandin vivoexperimental design for screening, and therapeutic efficacy in safety and human clinical trails for commercial outlet. Many of these commercially available compounds are crude preparations administered without performing human clinical trials. Recent methods are useful to standardize the extraction for scientific investigation of new phytochemicals and anti-microbials of traditionally used plants. It is concluded that once the local ethnomedical preparations of traditional sources are scientifically evaluated before dispensing they should replace existing drugs commonly used for the therapeutic treatment of infection. This method should be put into practice for future investigations in the field of ethnopharmacology, phytochemistry, ethnobotany and other biological fields for drug discovery.

Metabolomics of Healthy Berry Fruits

2019 ◽  
Vol 25 (37) ◽  
pp. 4888-4902 ◽  
Author(s):  
Gilda D'Urso ◽  
Sonia Piacente ◽  
Cosimo Pizza ◽  
Paola Montoro
Keyword(s):  
Biological Activities ◽  
Biologically Active ◽  
In Vivo Studies ◽  
Bioactive Metabolites ◽  
Active Metabolites ◽  
Positive Effects ◽  
Cell Functions ◽  
Berry Fruits

The consumption of berry-type fruits has become very popular in recent years because of their positive effects on human health. Berries are in fact widely known for their health-promoting benefits, including prevention of chronic disease, cardiovascular disease and cancer. Berries are a rich source of bioactive metabolites, such as vitamins, minerals, and phenolic compounds, mainly anthocyanins. Numerous in vitro and in vivo studies recognized the health effects of berries and their function as bioactive modulators of various cell functions associated with oxidative stress. Plants have one of the largest metabolome databases, with over 1200 papers on plant metabolomics published only in the last decade. Mass spectrometry (MS) and NMR (Nuclear Magnetic Resonance) are the most important analytical technologies on which the emerging ''omics'' approaches are based. They may provide detection and quantization of thousands of biologically active metabolites from a tissue, working in a ''global'' or ''targeted'' manner, down to ultra-trace levels. In the present review, we highlighted the use of MS and NMR-based strategies and Multivariate Data Analysis for the valorization of berries known for their biological activities, important as food and often used in the preparation of nutraceutical formulations.

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