A literature review on pharmacological aspects, docking studies, and synthetic approaches of quinazoline and quinazolinone derivatives.

Quinazoline and quinazolinone derivatives piqued medicinal chemistry interest in developing novel drug candidates owing to their pharmacological potential. They are important chemicals for the synthesis of a variety of physiologically significant and pharmacologically useful molecules. Quinazoline and quinazolinone derivatives have anticancer, anti-inflammatory, antidiabetic, anticonvulsant, antiviral, and antimicrobial potential. The increased understanding of quinazoline and quinazolinone derivatives in biological activities provides opportunities for new medicinal products. The present review focuses on novel advances in the synthesis of these important scaffolds and other medicinal aspects involving drug design, structure-activity relationship, and action mechanisms of quinazoline and quinazolinone derivatives to help in the development of new quinazoline and quinazolinone derivatives.

Enzyme Inhibition Assays for Monoamine Oxidase.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamines with two isoforms, namely, MAO-A and MAO-B, in mitochondrial outer membranes. These two types of MAO-A and MAO-B participate in changes in levels of neurotransmitter such as serotonin (5-hydroxytryptamine) and dopamine. Selective MAO-A inhibitors have been targeted for anti-depression treatment, while selective MAO-B inhibitors are targets of therapeutic agents for Alzheimer's disease and Parkinson's disease. For this reason, study on the development of MAO inhibitors has recently become important. Here, we describe methods of MAO activity assay, especially continuous spectrophotometric methods, which give relatively high accuracy. MAO-A and MAO-B can be assayed using kynuramine and benzylamine as substrates, respectively, at 316 nm and 250 nm, respectively, to measure their respective products, 4-hydroxyquinoline and benzaldehyde. Inhibition degree and pattern can be analyzed by using the Lineweaver-Burk and secondary plots in the presence of inhibitor, and reversibility of inhibitor can be determined by using the dialysis method.

AMCP Market Insights Health Plan Best Practice: Implementing continuous glucose monitoring to improve patient outcomes in diabetes.

Diabetes is a complex chronic condition that affects the body's ability to produce or use insulin effectively, resulting in elevated blood glucose levels. It is associated with various complications and comorbidities, significantly impacting both individuals and the health care system. Effective management involves a combination of lifestyle adjustments, medication adherence, monitoring, education, and support. The expanding use of continuous glucose monitoring (CGM) has been transformative in diabetes care, providing valuable real-time data and insights for better management. To understand the opportunity for health plans to support improved patient outcomes with CGM, AMCP sponsored a multifaceted approach to identify best practices consisting of expert interviews, a national payer survey, an expert panel workshop with clinical experts and managed care stakeholders, and a national webcast to communicate the program findings. This article summarizes current evidence for CGM to support managed care and payer professionals in making collaborative, evidence-based decisions to optimize outcomes among patients with diabetes. In addition, this review also presents the findings of a national payer survey and describes expert-supported health plan best practices around coverage and access to CGM.

Targeting GABA receptors with chalcone derivative compounds, what is the evidence?

INTRODUCTION: In medicinal chemistry, privileged structures have been frequently exploited as a successful template for drug discovery. Common simple scaffolds like chalcone are present in a wide range of naturally occurring chemicals. Chalcone exhibits extensive biological activity and has drawn attention in this context due to its function in the GABA receptor. Epilepsy and GABA receptors are related. It is a chronic neurological condition that affects globally. AREAS COVERED: Numerous neurological disorders, including anxiety and epilepsy, have been related to GABA, the brain's most prevalent inhibitory neurotransmitter. We go through the role of GABA receptors in anxiety and epilepsy in this review. The structure-activity relationship of chalcone and its derivatives on the GABA receptor is covered in our final section. EXPERT OPINION: GABA is a potential therapeutic target for issues associated with the nervous system. We talk about the potential effects of chalcone as a treatment for epilepsy and anxiety on the GABA receptor. Therefore, thorough research is necessary in this regard; the value of in silico tools in developing and enhancing GABA agonists is significant.

Introducing of novel class of pyrano[2,3-c]pyrazole-5-carbonitrile analogs with potent antimicrobial activity, DNA gyrase inhibition, and prominent pharmacokinetic and CNS toxicity profiles supported by molecular dynamic simulation.

Microbiological DNA gyrase is recognized as an exceptional microbial target for the innovative development of low-resistant and more effective antimicrobial drugs. Hence, we introduced a one-pot facile synthesis of a novel pyranopyrazole scaffold bearing different functionalities; substituted aryl ring, nitrile, and hydroxyl groups. All new analogs were characterized with full spectroscopic data. The antimicrobial screening for all analogs was assessed against standard strains of Gm + ve and Gm-ve through in vitro considers. The screened compounds displayed very promising MIC/MBC values against some of the bacterial strains with broad or selective antibacterial effects. Of these, 4j biphenyl analog showed 0.5-2/2-8 µg/mL MIC/MBC for suppression and killing of Gm + ve and Gm-ve strains. Moreover, the antimicrobial screening was assessed for the most potent analogs against certain highly resistant microbial strains. Consequently, DNA gyrase supercoiling assay was done for all analogs using ciprofloxacin as reference positive control. Obviously, the results showed a different activity profile with potent analog 4j with IC50 value 6.29 µg/mL better than reference drug 10.2 µg/mL. Additionally, CNS toxicity testing was done using the HiB5 cell line for attenuation of GABA/NMDA expression to both 4j and ciprofloxacin compounds that revealed better neurotransmitter modulation by novel scaffold. Importantly, docking and dynamic simulations were performed for the most active 4j analog to investigate its interaction with DNA binding sites, which supported the in vitro observations and compound stability with binding pocket. Finally, a novel scaffold pyranopyrazole was introduced as a DNA gyrase inhibitor with prominent antibacterial efficacy and low CNS side effect toxicity better than quinolones.Communicated by Ramaswamy H. Sarma.

The anticancer and EGFR-TK/CDK-9 dual inhibitory potentials of new synthetic pyranopyrazole and pyrazolone derivatives: X-ray crystallography, in vitro, and in silico mechanistic investigations.

Treatment options for the management of breast cancer are still inadequate. This inadequacy is attributed to the lack of effective targeted medications, often resulting in the recurrence of metastatic disorders. Cumulative evidence suggests that epidermal growth factor receptor (EGFR-TK) and cyclin-dependent kinases-9 (CDK-9) overexpression correlates with worse overall survival in breast cancer patients. Pyranopyrazole and pyrazolone are privileged options for the development of anticancer agents. Inspired by this proven scientific fact, we report here the synthesis of two new series of suggested anticancer molecules incorporating both heterocycles together with their characterization by IR, 1H NMR, 13C NMR, 13C NMR-DEPT, and X-ray diffraction methods. An attempt to get the pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3H-pyrazol-3-one instead. This unexpected result was confirmed by X-ray crystallographic analysis. All newly synthesized compounds were assessed for their anti-proliferative activity against two different human breast cancer cells, and the obtained results were compared with the reference drug Staurosporine. The target compounds revealed variable cytotoxicity with IC50 at a low micromolar range with superior selectivity indices. Target enzyme EGFR-TK and CDK-9 assays showed that compounds 22 and 23 effectively inhibited both biological targets with IC50 values of 0.143 and 0.121 µM, respectively. Molecular docking experiments and molecular dynamics simulation were also conducted to further rationalize the in vitro obtained results.Communicated by Ramaswamy H. Sarma.

Screening and Molecular Docking of Bioactive Metabolites of the Red Sea Sponge Callyspongia siphonella as Potential Antimicrobial Agents.

Marine sponges create a wide range of bioactive secondary metabolites, as documented throughout the year. Several bioactive secondary metabolites were isolated from different members of Callyspongia siphonella species. This study aimed for isolation and structural elucidation of major metabolites in order to investigate their diverse bioactivities such as antimicrobial and anti-biofilm activities. Afterwards, a molecular docking study was conducted, searching for the possible mechanistic pathway of the most bioactive metabolites. Extraction, fractionation, and metabolomics analysis of different fractions was performed in order to obtain complete chemical profile. Moreover, in vitro assessment of different bioactivities was performed, using recent techniques. Additionally, purification, structural elucidation of high features using recent chromatographic and spectroscopic techniques was established. Finally, AutoDock Vina software was used for the Pharmacophore-based docking-based analysis. As a result, DCM (dichloromethane) fraction exerted the best antibacterial activity using disc diffusion method; particularly against S. aureus with an inhibition zone of 6.6 mm. Compound 11 displayed a considerable activity against both MRSA (Methicillin-resistant Staphyllococcus aureus) and Staphyllococcus aureus with inhibition ratios of 50.37 and 60.90%, respectively. Concerning anti-biofilm activity, compounds 1 and 2 displayed powerful activity with inhibition ratios ranging from 39.37% to 70.98%. Pharmacophore-based docking-based analysis suggested elongation factor G (EF-G) to be a probable target for compound 11 (siphonellinol C) that showed the best in vitro antibacterial activity, offering unexplored potential for new drugs and treatment candidates.

Effects of radiation exposure on brain health: a state of the art and new challenges.

Good brain health refers to a condition in which a person may fully realize their talents and improve their psychological, emotional, cognitive, and behavioral functioning to cope with life's challenges. Various causes of CNS diseases are now being investigated. Radiation is one of the factors that affects the brain and causes a variety of problems. The emission or transmission of energy in the form of waves or particles via space or a material medium is known as radiation. Particle beams and electromagnetic waves are two types of ionizing radiation that have the potential to ionize atoms in a material (separating them into positively charged ions and negatively charged electrons). Radiation to the CNS can induce delayed puberty, which can lead to hyperprolactinemia, and the hypothalamic-pituitary axis can lead to gonadotropin deficit if the hypothalamic-pituitary axis is involved in the radiation field. Ionizing radiation is the most common kind of radiation. Here, we focus on the different effects of radiation on brain health. In this article, we will look at a variety of CNS diseases and how radiation affects each one, as well as how it affects the brain's numerous processes.

Assigning trabecular bone material properties in finite element models simulating the pelvis before and after the development of peri-prosthetic osteolytic lesions.

Estimating strain distribution in the acetabulum before and after the development of peri-prosthetic osteolytic lesions secondary to total hip arthroplasty may assist with understanding the pathogenesis of this condition. This could be achieved by performing patient-specific finite element analysis of (1) total hip arthroplasty recipients with developed acetabular osteolytic lesions, and (2) models simulating the patient's pelvis and implant immediately after primary surgery. State of the art patient-specific total hip arthroplasty finite element analysis simulations obtain trabecular bone material properties from Hounsfield units within computed tomography (CT) scans of patients. However, this is not feasible when an implant is already in situ due to metal artefact disruption and, in turn, incorrectly reproduced Hounsfield units. Therefore, alternative methods of assigning trabecular bone material properties within such models were tested and strain results compared. It was found that assigning set material properties throughout the trabecular bone geometry was sufficient for the desired application. Simulating the primary implant and pelvis requires geometric and material based assumptions. Therefore, comparisons were made between strain values obtained from simulated primary models, from state of the art methods using material properties obtained from intact bone within a CT scan, and from models with osteolytic lesions. Strain values found using the finite element models simulating the pelvis before osteolytic lesion developed were considerably closer to those found using state of the art methods than those found for the bone loss models. These models could be used to determine relationships between strain distribution and factors such as bone loss.

Conjugated Dienones from Differently Substituted Cinnamaldehyde as Highly Potent Monoamine Oxidase-B Inhibitors: Synthesis, Biochemistry, and Computational Chemistry.

Fifteen multiconjugated dienones (MK1-MK15) were synthesized and evaluated to determine their inhibitory activities against monoamine oxidases (MAOs) A and B. All derivatives were found to be potent and highly selective MAO-B inhibitors. Compound MK6, with an IC50 value of 2.82 nM, most effectively inhibited MAO-B, like MK12 (IC50 = 3.22 nM), followed by MK5, MK13, and MK14 (IC50 = 4.02, 4.24, and 4.89 nM, respectively). The selectivity index values of MK6 and MK12 for MAO-B over MAO-A were 7361.5 and 1780.5, respectively. Compounds MK6 and MK12 were competitive reversible inhibitors of MAO-B, with K i values of 1.10 ± 0.20 and 3.0 ± 0.27 nM, respectively. Cytotoxic studies showed that MK5, MK6, MK12, and MK14 exhibited low toxicities on Vero cells, with IC50 values of 218.4, 149.1, 99.96, and 162.3 µg/mL, respectively, which were much higher than those for their effective nanomolar-level concentrations. Also, MK5, MK6, MK12, and MK14 decreased cell damage in H2O2-induced cells via a significant scavenging effect of reactive oxygen species. Molecular modeling was performed to rationalize the potential inhibitory activities of MK5, MK6, MK12, and MK14 toward MAO-B and their possible binding mechanisms, showing high-affinity binding pocket interactions and conformation perturbations of the compounds with MAO-B, which were interpreted as the conformational dynamics of MAO-B. This study concluded that all the compounds tested were more potent MAO-B inhibitors than the reference drugs, and leading compounds could be further explored for their effectiveness in various kinds of neurodegenerative disorders.

In Silico Trial Approach for Biomedical Products: A Regulatory Perspective.

The modern pharmaceutical industry is transitioning from traditional methods to advanced technologies like artificial intelligence. In the current scenario, continuous efforts are being made to incorporate computational modeling and simulation in drug discovery, development, design, and optimization. With the advancement in technology and modernization, many pharmaceutical companies are approaching in silico trials to develop safe and efficacious medicinal products. To obtain marketing authorization for a medicinal product from the concerned National Regulatory Authority, manufacturers must provide evidence for the safety, efficacy, and quality of medical products in the form of in vitro or in vivo methods. However, more recently, this evidence was provided to regulatory agencies in the form of modeling and simulation, i.e., in silico evidence. Such evidence (computational or experimental) will only be accepted by the regulatory authorities if it considered as qualified by them, and this will require the assessment of the overall credibility of the method. One must consider the scrutiny provided by the regulatory authority to develop or use the new in silico evidence. The United States Food and Drug Administration and European Medicines Agency are the two regulatory agencies in the world that accept and encourage the use of modeling and simulation within the regulatory process. More efforts must be made by other regulatory agencies worldwide to incorporate such new evidence, i.e., modeling and simulation (in silico) within the regulatory process. This review article focuses on the approaches of in silico trials, the verification, validation, and uncertainty quantification involved in the regulatory evaluation of biomedical products that utilize predictive models.

Use of Real-Time Continuous Glucose Monitoring Improves Glycemic Control and Other Clinical Outcomes in Type 2 Diabetes Patients Treated with Less Intensive Therapy.

Objective: Use of real-time continuous glucose monitoring (rtCGM) has been shown to improve glycemic control in patients with type 2 diabetes (T2D) who are treated with intensive insulin therapy. However, most T2D patients are denied coverage for rtCGM due to failure to meet payer eligibility requirements: treatment with ≥3 insulin injections (or pump) and history of 4 × /day blood glucose testing. We investigated the relevance of these criteria to successful rtCGM use. Methods: This 6-month, prospective, interventional, single-arm study assessed the clinical effects of use rtCGM in patients with T2D treated with basal insulin only or noninsulin therapy. Primary outcomes were changes in HbA1c, average glucose, glycemic variability (% coefficient of variation), and percent of time in range (%TIR), below range (%TBR) and above range (%TAR). Results: Thirty-eight patients were included in the analysis (10.1% ± 1.8% HbA1c, 54.7 ± 10.2 years, 35.6 ± 6.4 body mass index). At 6 months, we observed reductions in HbA1c (-3.0% ± 1.3%, P < 0.001) and average glucose (-23.6 ± 38.8, P < 0.001). %TIR increased 15.2 ± 22.3, from 57.0 ± 29.9 to 72.2 ± 23.6, P < 0.001, with all patients maintaining %TBR targets (<4% at 70 mg/dL, <1% at <54 mg/dL). No changes in glycemic variability were observed. The greatest improvements in %TIR and %TAR were seen in patients treated with ≤1 medication. Conclusions: rtCGM use was associated with significant glycemic improvements in T2D patients treated with basal insulin only or noninsulin therapy. Given the growing body of evidence supporting rtCGM use in this population, insurance eligibility criteria should be modified to expand rtCGM use by T2D patients treated with less intensive therapies.

Gene Therapy Approach with an Emphasis on Growth Factors: Theoretical and Clinical Outcomes in Neurodegenerative Diseases.

The etiology of many neurological diseases affecting the central nervous system (CNS) is unknown and still needs more effective and specific therapeutic approaches. Gene therapy has a promising future in treating neurodegenerative disorders by correcting the genetic defects or by therapeutic protein delivery and is now an attraction for neurologists to treat brain disorders, like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar ataxia, epilepsy, Huntington's disease, stroke, and spinal cord injury. Gene therapy allows the transgene induction, with a unique expression in cells' substrate. This article mainly focuses on the delivering modes of genetic materials in the CNS, which includes viral and non-viral vectors and their application in gene therapy. Despite the many clinical trials conducted so far, data have shown disappointing outcomes. The efforts done to improve outcomes, efficacy, and safety in the identification of targets in various neurological disorders are also discussed here. Adapting gene therapy as a new therapeutic approach for treating neurological disorders seems to be promising, with early detection and delivery of therapy before the neuron is lost, helping a lot the development of new therapeutic options to translate to the clinic.

A semiautomated method to quantitatively assess osteolytic lesion volume and bone mineral density within acetabular regions of interest from CT.

The objectives of this study were to (1) develop a semiautomated method to obtain lesion volume and bone mineral density (BMD) in terms of Hounsfield units from pelvic computed tomography (CT) scans in three regions of interest, and (2) assess accuracy and reliability of the method based on cadaveric CT scans. Image artefacts due to metal implants reduce CT clarity and are more severe with more than one implant in situ. Therefore, accuracy and reliability tests were performed with varying numbers of total hip arthroplasties implanted. To test the accuracy of lesion size measurements, microcomputed tomography was used as a reference. Mean absolute error ranged from 36 to 284 mm3 after five measurements. Intra- and inter-operator reliability of the entire method was measured for a selection of parameters. All coefficient of variation values were good to excellent for CT scans of the native pelvic anatomy and a CT scans of the same pelvis with one and two implants in situ. Accuracy of quantifying lesion volume decreased with decreasing CT image clarity by 0.6%-3.6% mean absolute relative error. Reliability of lesion volume measurement decreased with decreasing CT clarity. This was also the case for reliability of BMD measurements in the region most disrupted by metal artefact. The presented method proposes an approach for quantifying bone loss which has been proven to be accurate, reliable, and clinically applicable.

Trimethoxy Crown Chalcones as Multifunctional Class of Monoamine Oxidase Enzyme Inhibitors.

BACKGROUND: Chalcones with methoxy substituent are considered as a promising framework for the inhibition of monoamine oxidase (MAO) enzymes. METHODS: A series of nine trimethoxy substituted chalcones (TMa-TMi) was synthesized and evaluated as a multifunctional class of MAO inhibitors. All the synthesized compounds were investigated for their in vitro MAO inhibition, kinetics, reversibility, blood-brain barrier (BBB) permeation, and cytotoxicity and antioxidant potentials. RESULTS: In the present study, compound (2E)-3-(4-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)prop- 2-en-1-one (TMf) was provided with a MAO-A inhibition constant value equal to 3.47±0.09 µM with a selectivity of 0.008, thus comparable to that of moclobemide, a well known potent hMAOA inhibitor (SI=0.010). Compound (2E)-3-(4-bromophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2- en-1-one (TMh) show good MAO-B inhibition with inhibition constant of 0.46±0.009 µM. The PAMPA assay demonstrated that all the synthesized derivatives can cross the BBB successfully. The cytotoxicity studies revealed that TMf and TMh have 88.22 and 80.18 % cell viability at 25 µM. Compound TMf appeared as the most promising antioxidant molecule with IC50 values, relative to DPPH and H2O2 radical activities equal to 6.02±0.17 and 7.25±0.07 µM. To shed light on the molecular interactions of TMf and TMh towards MAO-A and MAO-B, molecular docking simulations and MM/GBSA calculations have been carried out. CONCLUSION: The lead molecules TMf and TMh with multi-functional nature can be further employed for the treatment of various neurodegenerative disorders and depressive states.

The Role of Mitochondrial Genes in Neurodegenerative Disorders.

Mitochondrial disorders are clinically heterogeneous, resulting from nuclear gene and mitochondrial mutations that disturb the mitochondrial functions and dynamics. There is a lack of evidence linking mtDNA mutations to neurodegenerative disorders, mainly due to the absence of noticeable neuropathological lesions in postmortem samples. This review describes various gene mutations in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. These abnormalities, including PINK1, Parkin, and SOD1 mutations, seem to reveal mitochondrial dysfunctions due to either mtDNA mutation or deletion, the mechanism of which remains unclear in depth.

Ameliorative effect of ethoxylated chalcone-based MAO-B inhibitor on behavioural predictors of haloperidol-induced Parkinsonism in mice: evidence of its antioxidative role against Parkinson's diseases.

Parkinson's disease is a progressive neurodegenerative disorder that affects mostly elderly people above the age of 60. Previously, we have reported that the ethoxylated chalcone derivative (E)-1-(4-ethoxyphenyl)-3-(fluorophenyl)prop-2-en-1-one (E7) showed potent, reversible, and competitive MAO-B inhibition with an IC50 value of 0.053 µm. The present study aims to investigate the anti-Parkinson activity of compound E7 in a haloperidol-induced animal model of mice. The disease was induced with haloperidol (1 mg/kg, intraperitoneal route) once daily for 21 days. E7 was given at dose levels of 10, 20, and 30 mg/kg/day for 21 days, consecutively. Behavioural tests were carried out during and at the end of the study. Biochemical analyses such as oxidative stress biomarkers and neurotransmitters were quantified on the brain homogenate at the end of the study. Behavioural results showed that there is a marked improvement in locomotor activity and motor coordination in the treatment group. Oxidative stress biomarkers such as SOD, CAT, and GSH levels were increased dose-dependently with a maximum at 30 mg/kg, whereas the dose-dependent decrease (30 mg/kg) in the MDA and nitrite levels were observed in the treatment groups. Levels of neurotransmitters, such as dopamine, serotonin, and noradrenaline, were increased in the treatment groups while dopamine and noradrenaline levels were more than in the standard treated group. MAO-B level was also decreased dose dependently in the treatment group in comparison with the control group. Based on the findings, it was concluded that the E7 compound exhibited anti-Parkinson activity which was more evident at 30 mg/kg oral dose as evaluated by the haloperidol-induced animal model of mice.

Piperazine-substituted chalcones: a new class of MAO-B, AChE, and BACE-1 inhibitors for the treatment of neurological disorders.

Eleven piperazine-containing 1,3-diphenylprop-2-en-1-one derivatives (PC1-PC11) were evaluated for their inhibitory activities against monoamine oxidases (MAOs), cholinesterases (ChEs), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with a view toward developing new treatments for neurological disorders. Compounds PC10 and PC11 remarkably inhibited MAO-B with IC50 values of 0.65 and 0.71 µM, respectively. Ten of the eleven compounds weakly inhibited AChE and BChE with > 50% of residual activities at 10 µM, although PC4 inhibited AChE by 56.6% (IC50 = 8.77 µM). Compound PC3 effectively inhibited BACE-1 (IC50 = 6.72 µM), and PC10 and PC11 moderately inhibited BACE-1 (IC50 =14.9 and 15.3 µM, respectively). Reversibility and kinetic studies showed that PC10 and PC11 were reversible and competitive inhibitors of MAO-B with Ki values of 0.63 ± 0.13 and 0.53 ± 0.068 µM, respectively. ADME predictions for lead compounds revealed that PC10 and PC11 have central nervous system (CNS) drug-likeness. Molecular docking simulations showed that fluorine atom and trifluoromethyl group on PC10 and PC11, respectively, interacted with the substrate cavity of the MAO-B active site. Our results suggested that PC10 and PC11 can be considered potential candidates for the treatment of neurological disorders such as Alzheimer's disease and Parkinson's disease.

An Agathokakological Tale of Δ9-THC: Exploration of Possible Biological Targets.

Δ9-Tetrahydrocannabinol (Δ9-THC), the active phytocannabinoid in cannabis, is virtually an adjunct to the endogenous endocannabinoid signaling system. By interacting with G-proteincoupled receptors CB1 and CB2, Δ9-THC affects peripheral and central circulation by lowering sympathetic activity, altering gene expression, cell proliferation, and differentiation, decreasing leukocyte migration, modulating neurotransmitter release, thereby modulating cardiovascular functioning, tumorigenesis, immune responses, behavioral and locomotory activities. Δ9-THC effectively suppresses chemotherapy-induced vomiting, retards malignant tumor growth, inhibits metastasis, and promotes apoptosis. Other mechanisms involved are targeting cell cycle at the G2-M phase in human breast cancer, downregulation of E2F transcription factor 1 (E2F1) in human glioblastoma multiforme, and stimulation of ER stress-induced autophagy. Δ9-THC also plays a role in ameliorating neuroinflammation, excitotoxicity, neuroplasticity, trauma, and stroke and is associated with reliving childhood epilepsy, brain trauma, and neurodegenerative diseases. Δ9-THC via CB1 receptors affects nociception, emotion, memory, and reduces neuronal excitability and excitotoxicity in epilepsy. It also increases renal blood flow, reduces intraocular pressure via a sympathetic pathway, and modulates hormonal release, thereby decreasing the reproductive function and increasing glucose metabolism. Versatile medical marijuana has stimulated abundant research demonstrating substantial therapeutic promise, suggesting the possibilities of first-in-class drugs in diverse therapeutic segments. This review represents the current pharmacological status of the phytocannabinoid, Δ9-THC, and synthetic analogs in cancer, cardiovascular, and neurodegenerative disorders.

Exploring the Therapeutic Potentials of Highly Selective Oxygenated Chalcone Based MAO-B Inhibitors in a Haloperidol-Induced Murine Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder of dopaminergic, noradrenergic, and serotonergic systems, in which dopamine, noradrenaline, and serotonin levels are depleted and lead to the development of motor and non-motor symptoms such as tremor, bradykinesia, weight changes, fatigue, depression, and visual hallucinations. Therapeutic strategies place much focus on dopamine replacement and the inhibition of dopamine metabolism. The present study was based on the known abilities of chalcones to act as molecular scaffolds that selectively inhibit MAO-B with the added advantage of binding reversibly. Recently, we synthesized a series of 26 chalcone compounds, amongst which (2E)-1-(2H-1,3-benzodioxol-5-yl)-3-(4-fluorophenyl)prop-2-en-1-one (O10) and (2E)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(4-fluorophenyl)prop-2-en-1-one (O23) most inhibited MAO-B. Hence, the present study was performed to explore the molecular mechanisms responsible for the neuroprotective effect of O10 and O23 at varying doses such as 10, 20, and 30 mg/kg each in a haloperidol-induced murine model of PD. Both compounds were effective (though O23 was the more effective) at ameliorating extrapyramidal and non-motor symptoms in the model and improved locomotory and exploratory behaviors, reduced oxidative stress markers, and enhanced antioxidant marker and neurotransmitter levels. Furthermore, histopathological studies showed O10 and O23 both reduced neurofibrillary tangles and plaques to almost normal control levels.