Biological characterization of PM226, a chromenoisoxazole, as a selective CB2 receptor agonist with neuroprotective profile.

Abstract:

:Cannabinoids have emerged as promising neuroprotective agents due to their capability to activate specific targets, which are involved in the control of neuronal homeostasis and survival. Specifically, those ligands that selectively target and activate the CB2 receptor may be useful for their anti-inflammatory and neuroprotective properties in various neurological disorders, with the advantage of being devoid of psychotropic effects associated with the activation of CB1 receptors. The aim of this work has been to investigate the neuroprotective properties of 7-(1,1-dimethylheptyl)-4,4-dimethyl-9-methoxychromeno[3,4-d]isoxazole (PM226), a compound derived from a series of chromeno-isoxazoles and -pyrazoles, which seems to have a promising profile related to the CB2 receptor. The compound binds selectively to this receptor with an affinity in the nanomolar range (Ki=12.8±2.4nM). It has negligible affinity for the CB1 receptor (Ki>40000nM) and no activity at the GPR55. PM226 was also evaluated in GTPγS binding assays specific to the CB2 receptor showing agonist activity (EC50=38.67±6.70nM). In silico analysis of PM226 indicated that it has a good pharmacokinetic profile and a predicted ability to cross the blood-brain barrier. Next, PM226 was investigated in an in vitro model to explore its anti-inflammatory/neuroprotective properties. Conditioned media were collected from LPS-stimulated cultures of BV2 microglial cell line in the absence or presence of different doses of PM226, and then media were added to cultured M213-2O neuronal cells to record their influence on cell viability evaluated using MTT assays. As expected, cell viability was significantly reduced by the exposure to these conditioned media, while the addition of PM226 attenuated this reduction in a dose-dependent manner. This effect was reversed by co-incubating with the CB2 antagonist SR144528, thus confirming the involvement of CB2 receptors, whereas the addition of PM226 to neuronal cultures instead cultured BV2 cells was not effective. PM226 has also been studied in an in vivo model of mitochondrial damage generated by intrastriatal application of malonate in rats. MRI analysis showed that PM226 administration decreased the volume of the striatal lesion caused by malonate, effect that was confirmed after the histopathological evaluation (Nissl staining, Iba-1 immunostaining and TUNEL assay) of striatal sections derived from malonate-lesioned rats in the absence or presence of PM226. Again, the beneficial effects of PM226 were dependent on the activation of CB2 receptors as they were reversed by blocking these receptors with AM630. Overall, PM226 has shown to have a promising neuroprotective profile derived from its ability to selectively activate CB2 receptor, so that it could be a useful disease-modifying agent in those neurodegenerative pathologies in which the activation of these receptors may have therapeutic value.

journal_name

Pharmacol Res

journal_title

Pharmacological research

authors

Gómez-Cañas M,Morales P,García-Toscano L,Navarrete C,Muñoz E,Jagerovic N,Fernández-Ruiz J,García-Arencibia M,Pazos MR

doi

10.1016/j.phrs.2016.03.021

subject

Has Abstract

pub_date

2016-08-01 00:00:00

pages

205-215

eissn

1043-6618

issn

1096-1186

pii

S1043-6618(16)30208-0

journal_volume

110

pub_type

杂志文章
  • Meta-analysis on outcome-worsening comorbidities of COVID-19 and related potential drug-drug interactions.

    abstract::Drug-drug interactions (DDI) potentially occurring between medications used in the course of COVID-19 infection and medications prescribed for the management of underlying comorbidities may cause adverse drug reactions (ADRs) contributing to worsening of the clinical outcome in affected patients. First, we conducted a...

    journal_title:Pharmacological research

    pub_type: 杂志文章,meta分析

    doi:10.1016/j.phrs.2020.105250

    authors: Awortwe C,Cascorbi I

    更新日期:2020-11-01 00:00:00

  • The influence of midazolam and flumazenil on rat brain slices oxygen consumption.

    abstract::This study investigated the impact of benzodiazepine receptor agonist, midazolam and antagonist, flumazenil, on the rat frontal cortex slices oxygen consumption (QO(2)), in presence and absence of gamma-aminobutyric acid (GABA). QO(2) was polarographically determined, using the biological oxygen monitor. As it was pre...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1016/s1043-6618(02)00289-x

    authors: Obradović DI,Savić MM,Andjelković DS,Ugresić ND,Bokonjić DR

    更新日期:2003-02-01 00:00:00

  • EEG and behavioural effects of polyamines (spermine and spermidine) on rabbits.

    abstract::The EEG and behavioural changes induced by the administration of polyamines (spermine and spermidine) were studied in rabbit. Spermine and spermidine were administered at different doses (200 and 400 micrograms) into the mesencephalic ventricle (i.c.v.) both as a bolus and in constant perfusion (60 min duration). We a...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1016/1043-6618(90)90754-2

    authors: Bo P,Giorgetti A,Camana C,Savoldi F

    更新日期:1990-07-01 00:00:00

  • Modulation of inflammatory paw oedema by cysteamine in the rat.

    abstract::Cysteamine, a potent somatostatin depletor, was used in the present study to investigate the role of endogenous somatostatin in acute peripheral inflammation. The acute inflammation was induced by intraplantar injection of carrageenan (1%), histamine (5 micromol), or formalin (2.5%) in the rat hind paw. The induced in...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1006/phrs.2002.0955

    authors: Salam OM

    更新日期:2002-04-01 00:00:00

  • MicroRNAs in chronic airway diseases: Clinical correlation and translational applications.

    abstract::MicroRNAs (miRNAs) are short single-stranded RNAs that have pivotal roles in disease pathophysiology through transcriptional and translational modulation of important genes. It has been implicated in the development of many diseases, such as stroke, cardiovascular conditions, cancers and inflammatory airway diseases. ...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审

    doi:10.1016/j.phrs.2020.105045

    authors: Tan BWQ,Sim WL,Cheong JK,Kuan WS,Tran T,Lim HF

    更新日期:2020-10-01 00:00:00

  • A review of therapeutic agents and Chinese herbal medicines against SARS-COV-2 (COVID-19).

    abstract::The epidemic of pneumonia (COVID-19) caused by novel coronavirus (SARS-CoV-2) infection has been listed as a public health emergency of international concern by the World Health Organization (WHO), and its harm degree is defined as a global "pandemic". At present, the efforts of various countries focus on the rapid di...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审

    doi:10.1016/j.phrs.2020.104929

    authors: Huang F,Li Y,Leung EL,Liu X,Liu K,Wang Q,Lan Y,Li X,Yu H,Cui L,Luo H,Luo L

    更新日期:2020-08-01 00:00:00

  • Changes in cell morphology guide identification of tubulin as the off-target for protein kinase inhibitors.

    abstract::In the field of kinase inhibitors for applications in cancer research, tubulin is emerging as a targeted cellular protein that can significantly contribute to their activities. However, investigation of kinase inhibitors beyond the kinome is an area often neglected. Herein, we describe the results of pharmacological s...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1016/j.phrs.2018.06.023

    authors: Hoque M,Abbassi RH,Froio D,Man J,Johns TG,Stringer BW,Day BW,Pajic M,Kassiou M,Munoz L

    更新日期:2018-08-01 00:00:00

  • Behavioural activity of (S)-3,5-DHPG, a selective agonist of group I metabotropic glutamate receptors.

    abstract::The influence of intracerebroventricular (i.c.v.) injections of (S)-3,5-dihydroxyphenyl-glycine (S)-3,5-DHPG, a selective agonist of group I metabotropic glutamate receptors (mGluRs), on the activity of the central nervous system was examined in male rats. (S)-3,5-DHPG at doses of 25, 50 and 100 nmol significantly att...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1006/phrs.2000.0683

    authors: Zalewska-Wińska A,Wiśniewski K

    更新日期:2000-09-01 00:00:00

  • Control of salt intake by steroids and cerebral peptides.

    abstract::Steroids (aldosterone and testosterone) and peptides of cerebral origin (angiotensin II and the tachykinins) control the salt intake of the rat. They arouse or suppress the behaviour and produce life-long enhancements of NaCl intake. Need-induced salt intake (salt appetite or salt hunger), which is the consequence of ...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审

    doi:10.1016/1043-6618(92)91380-y

    authors: Epstein AN

    更新日期:1992-02-01 00:00:00

  • Weight control and prevention of metabolic syndrome by green tea.

    abstract::Green tea (Camellia sinensis, Theaceace) is the second most popular beverage in the world and has been extensively studied for its putative disease preventive effects. Green tea is characterized by the presence of a high concentrations of polyphenolic compounds known as catechins, with (-)-epigallocatechin-3-gallate (...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审

    doi:10.1016/j.phrs.2010.12.013

    authors: Sae-tan S,Grove KA,Lambert JD

    更新日期:2011-08-01 00:00:00

  • Novel indole-based compounds that differentiate alkylindole-sensitive receptors from cannabinoid receptors and microtubules: Characterization of their activity on glioma cell migration.

    abstract::Indole-based compounds, such as the alkyl-indole (AI) compound WIN55212-2, activate the cannabinoid receptors, CB1 and CB2, two well-characterized G protein-coupled receptors (GPCR). Reports indicate that several indole-based cannabinoid agonists, including WIN55212-2, lack selectivity and interact with at least two a...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1016/j.phrs.2016.10.025

    authors: Fung S,Xu C,Hamel E,Wager-Miller JB,Woodruff G,Miller A,Sanford C,Mackie K,Stella N

    更新日期:2017-01-01 00:00:00

  • The influence of lidocaine and verapamil on haemodynamic parameters after intravenous administration of midazolam in rabbits.

    abstract::Cardiac arrhythmia can be a serious complication during general anaesthesia of patients suffering from cardiac arrhythmias and using antiarrhythmic drugs. The aim of the present experiments was to establish the way in which lidocaine and verapamil influence haemodynamic parameters of rabbits after midazolam anaesthesi...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1006/phrs.1998.0464

    authors: Wiktorowska A,Owczarek J,Orszulak-Michalak D

    更新日期:1999-06-01 00:00:00

  • Inhibition of poly(ADP-ribose) polymerase attenuates lung tissue damage after hind limb ischemia-reperfusion in rats.

    abstract::The objective of this study was to investigate the effects of 3-aminobenzamide (3-AB) on tissue damage in lung after hind limb ischemia-reperfusion (I/R), by assessing blood biochemical assay and histopathological analysis. Thirty-five adult Wistar rats were divided into five groups. After application of anaesthesia b...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1016/j.phrs.2004.11.007

    authors: Koksel O,Yildirim C,Cinel L,Tamer L,Ozdulger A,Bastürk M,Degirmenci U,Kanik A,Cinel I

    更新日期:2005-05-01 00:00:00

  • Biochemical changes on the cardioprotective effect of nicorandil and amlodipine during experimental myocardial infarction in rats.

    abstract::The synergistic protective effect of nicorandil (KATP channel opener) and amlodipine (calcium channel blocker) on mitochondrial respiration and mitochondrial lipid contents were examined on isoproterenol-induced myocardial infarction in rats. The rats given isoproterenol (150 mg kg(-1) daily, i.p.) for 2 days showed s...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1016/s1043-6618(03)00223-8

    authors: Sathish V,Ebenezar KK,Devaki T

    更新日期:2003-12-01 00:00:00

  • Statins in chronic kidney disease and kidney transplantation.

    abstract::HMG-CoA reductase inhibitors (statins) have been shown to improve cardiovascular (CV) outcomes in the general population as well as in patients with cardiovascular disease (CVD). Statins' beneficial effects have been attributed to both cholesterol-lowering and cholesterol-independent "pleiotropic" properties. By their...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审

    doi:10.1016/j.phrs.2014.06.011

    authors: Kassimatis TI,Goldsmith DJ

    更新日期:2014-10-01 00:00:00

  • Anticholinergic action of clonidine in rats with sinoaortic denervation.

    abstract::A study was carried out relating to the anticholinergic action of clonidine on the cardiovascular responses to i.c.v. injection of neostigmine, a quaternary anticholinesterase, in conscious sham-operated animals and rats with sinoaortic denervation, 7 days after the corresponding operation. Neostigmine (0.1-1 microgra...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1006/phrs.1997.0295

    authors: Taira CA

    更新日期:1998-04-01 00:00:00

  • Disease modifying therapies in type 1 diabetes: Where have we been, and where are we going?

    abstract::With more than four decades of clinical research and 25 years of clinical trials, much is known about the natural history of T1D before and after clinical diagnosis. We know that autoimmunity occurs early in life, that islet autoimmunity inevitably leads to clinically overt disease, and that some immune therapies can ...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审

    doi:10.1016/j.phrs.2015.02.002

    authors: Lord S,Greenbaum CJ

    更新日期:2015-08-01 00:00:00

  • Tumor deconstruction as a tool for advanced drug screening and repositioning.

    abstract::A major focus of contemporary drug screening strategies is the identification of novel anticancer compounds, which often results in underutilization of resources. Current drug evaluation involves in vivo tumor (xenograft) regression as proof-of-principle for cytotoxicity (POC). However, this end-point lacks any assess...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1016/j.phrs.2016.07.018

    authors: Naik RR,Luo T,Kohandel M,Bapat SA

    更新日期:2016-09-01 00:00:00

  • Altered expression of connexin 43 and related molecular partners in a pig model of left ventricular dysfunction with and without dipyrydamole therapy.

    abstract::Gap junctions (GJ) mediate electrical coupling between cardiac myocytes, allowing the spreading of the electrical wave responsible for synchronized contraction. GJ function can be regulated by modulation of connexon densities on membranes, connexin (Cx) phosphorylation, trafficking and degradation. Recent studies have...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1016/j.phrs.2015.03.015

    authors: Del Ry S,Moscato S,Bianchi F,Morales MA,Dolfi A,Burchielli S,Cabiati M,Mattii L

    更新日期:2015-05-01 00:00:00

  • Muscarinic M(2) receptors are not primarily involved in the contraction of guinea-pig gallbladder smooth muscle.

    abstract::The presence of M(1)-M(4) receptors in guinea-pig gallbladder smooth muscle cells has been reported recently. The majority of these receptors are said to be of M(2) subtype. However, there are controversial reports about the functional muscarinic receptors that mediate contraction in this tissue. Similar to gallbladde...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1006/phrs.1999.0536

    authors: Akici A,Karaalp A,Skender E,El-Fakahany EE,Oktay S

    更新日期:1999-11-01 00:00:00

  • The abundance of the long intergenic non-coding RNA 01087 differentiates between luminal and triple-negative breast cancers and predicts patient outcome.

    abstract::The molecular complexity of human breast cancer (BC) renders the clinical management of the disease challenging. Long non-coding RNAs (lncRNAs) are promising biomarkers for BC patient stratification, early detection, and disease monitoring. Here, we identified the involvement of the long intergenic non-coding RNA 0108...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1016/j.phrs.2020.105249

    authors: De Palma FDE,Del Monaco V,Pol JG,Kremer M,D'Argenio V,Stoll G,Montanaro D,Uszczyńska-Ratajczak B,Klein CC,Vlasova A,Botti G,D'Aiuto M,Baldi A,Guigó R,Kroemer G,Maiuri MC,Salvatore F

    更新日期:2020-11-01 00:00:00

  • Effects of antiemetic drugs on glucose 6-phosphate dehydrogenase and some antioxidant enzymes.

    abstract::The aim of this study was to investigate effect of antiemetics on G6PD and antioxidant enzymes. Antiemetics are currently being used to reduce or prevent nausea and vomiting in patients. This is the first study to show effect of antiemetics on glucose-6-phosphate dehydrogenase (G6PD) and antioxidant enzyme activities....

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1016/j.phrs.2004.05.007

    authors: Ozmen I,Küfrevioglu OI

    更新日期:2004-11-01 00:00:00

  • Hypochlorous acid-induced responses in sheep isolated pulmonary artery rings.

    abstract::The formation of reactive oxygen species (ROS) appears to play a significant role in many pathological states including cystic fibrosis and asthma. Although stimulated inflammatory cells represent a major source of oxygen metabolites and these cells are able to generate the potent oxidant hypochlorous acid (HOCl) effe...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1006/phrs.1999.0628

    authors: Turan NN,Demiryürek AT,Kanzik I

    更新日期:2000-05-01 00:00:00

  • The role of PPARs in modulating cardiac metabolism in diabetes.

    abstract::Diabetes mellitus is an important risk factor for the development of cardiovascular disease. The impact of diabetes on the heart in part resides in the changes in metabolic fuel availability evoked by lack of insulin or resistance to its action. This review addresses how the metabolic abnormalities associated with poo...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审

    doi:10.1016/j.phrs.2009.04.006

    authors: Holness MJ,Samsuddin S,Sugden MC

    更新日期:2009-09-01 00:00:00

  • Postmenopausal exogenous hormone therapy and Melanoma risk in women: A systematic review and time-response meta-analysis.

    abstract::A favourable option to management symptoms during menopausal transition is menopausal hormone therapy (MHT) but relation among MHT and risk of melanoma is controversial. This study aims to identify, analyse and present the evidence surrounding post-menopausal exogenous hormone therapy and the risk for melanoma in wome...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审

    doi:10.1016/j.phrs.2020.105182

    authors: Tang X,Zhang H,Cui Y,Wang L,Wang Z,Zhang Y,Huo J,Cai J,Rinaldi G,Bhagavathula AS,Xiaopeng Y

    更新日期:2020-10-01 00:00:00

  • Antibody modulation: Limiting the efficacy of therapeutic antibodies.

    abstract::Monoclonal antibodies (mAb) have revolutionised the way in which we treat disease. From cancer to autoimmunity, antibody therapy has been responsible for some of the most impressive clinical responses observed in the last 2 decades. A key component of this success has been their generally low levels of toxicity, and u...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1016/j.phrs.2015.07.003

    authors: Vaughan AT,Cragg MS,Beers SA

    更新日期:2015-09-01 00:00:00

  • Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases.

    abstract::The Janus kinase (JAK) family of non-receptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase-2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that regulates the adjacent protein kinase domain (JH1). JAK1/2 and TYK2 are ubiquitously expressed whereas JAK3 is...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审

    doi:10.1016/j.phrs.2016.07.038

    authors: Roskoski R Jr

    更新日期:2016-09-01 00:00:00

  • Effect of vigabatrin on contractile response to arachidonic acid and prostaglandins in smooth muscle preparations and platelet aggregation in experimental laboratory animals.

    abstract::Gamma-vinyl GABA (vigabatrin; VGB), an irreversible inhibitor of GABA-transaminase, was evaluated for its effect on the contractile responses to PGE(2) or its precursor arachidonic acid (AA) in guinea pig ileum (GPI) and non-pregnant rat uterus. Rationale behind this study was the rise in gamma-aminobutyric acid (GABA...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1016/s1043-6618(03)00045-8

    authors: Raza M,Al-Shabanah OA

    更新日期:2003-06-01 00:00:00

  • A case-control study of the effects of hydroxyurea on circulating cortisol levels in patients with acute myelogenous leukemia and chronic myeloproliferative disorders.

    abstract::We have shown previously that the antitumor drug, hydroxyurea (HU) is able to induce dose-dependent increases in plasma corticosterone levels in the rat. The drug was administered early in the morning, when the levels of circulating glucocorticoids are low in this species. Normally, in humans under physiological condi...

    journal_title:Pharmacological research

    pub_type: 临床试验,杂志文章

    doi:10.1006/phrs.2000.0709

    authors: Navarra P,Aloe-Spiriti MA,Boccarini F,Montefusco E,Latagliata R,Preziosi P,Petti MC

    更新日期:2000-10-01 00:00:00

  • Evidence for oxidative stress in the hepatic mitochondria of bile duct ligated rats.

    abstract::Lipid peroxidation increased both in the liver homogenates and in the hepatic mitochondrial fraction of bile duct ligated (BDL)-rats. Although mitochondrial superoxide dismutase (SOD) activity did not change in the liver, glutathione (GSH) levels and glutathione peroxidase (GSH-Px) activity decreased in hepatic mitoch...

    journal_title:Pharmacological research

    pub_type: 杂志文章

    doi:10.1006/phrs.1997.0225

    authors: Alptekin N,Mehmetçik G,Uysal M,Aykaç-toker G

    更新日期:1997-09-01 00:00:00