Publications by authors named "Antonella Brizzi"

42 Publications

GPR120/FFAR4 Pharmacology: Focus on Agonists in Type 2 Diabetes Mellitus Drug Discovery.

J Med Chem 2021 04 10;64(8):4312-4332. Epub 2021 Apr 10.

Department of Biotechnology, Chemistry, and Pharmacy, DoE 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.

The G-protein coupled receptors (GPCRs) activated by free fatty acids (FFAs) have emerged as new and exciting drug targets, due to their plausible translation from pharmacology to medicines. This perspective aims to report recent research about GPR120/FFAR4 and its involvement in several diseases, including cancer, inflammatory conditions, and central nervous system disorders. The focus is to highlight the importance of GPR120 in Type 2 diabetes mellitus (T2DM). GPR120 agonists, useful in T2DM drug discovery, have been widely explored from a structure-activity relationship point of view. Since the identification of the first reported synthetic agonist TUG-891, the research has paved the way for the development of TUG-based molecules as well as new and different chemical entities. These molecules might represent the starting point for the future discovery of GPR120 agonists as antidiabetic drugs.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154576PMC
April 2021

Pinocembrin and its linolenoyl ester derivative induce wound healing activity in HaCaT cell line potentially involving a GPR120/FFA4 mediated pathway.

Bioorg Chem 2021 03 27;108:104657. Epub 2021 Jan 27.

Department of Pharmacy, Health and Nutritional Sciences - DoE 2018-2022, University of Calabria, Ed. Polifunzionale, 87036 Arcavacata di Rende (CS), Italy.

Wound healing represents an urgent need from the clinical point of view. Several diseases result in wound conditions which are difficult to treat, such as in the case of diabetic foot ulcer. Starting from there, the medicinal research has focused on various targets over the years, including GPCRs as new wound healing drug targets. In line with this, GPR120, known to be an attractive target in type 2 diabetes drug discovery, was studied to finalize the development of new wound healing agents. Pinocembrin (HW0) was evaluated as a suitable compound for interacting with GPR120, and was hybridized with fatty acids, which are known endogenous GPR120 ligands, to enhance the wound healing potential and GPR120 interactions. HW0 and its 7-linolenoyl derivative (HW3) were found to be innovative wound healing agents. Immunofluorescence and functional assays suggested that their activity was mediated by GPR120, and docking simulations showed that the compounds could share the same pocket occupied by the known GPR120 agonist, TUG-891.
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http://dx.doi.org/10.1016/j.bioorg.2021.104657DOI Listing
March 2021

A multitarget semi-synthetic derivative of the flavonoid morin with improved in vitro vasorelaxant activity: Role of Ca1.2 and K1.1 channels.

Biochem Pharmacol 2021 03 26;185:114429. Epub 2021 Jan 26.

Department of Pharmacy, Health and Nutritional Sciences, DoE 2018-2022, University of Calabria, Edificio Polifunzionale, 87036 Arcavacata di Rende, CS, Italy.

Ca1.2 channels play a fundamental role in the regulation of vascular smooth muscle tone. The aim of the present study was to synthesize morin derivatives bearing the nitrophenyl moiety of dihydropyridine Ca antagonists to increase the flavonoid vasorelaxant activity. The effects of morin and its derivatives were assessed on Ca1.2 and K1.1 channels, both in vitro and in silico, as well as on the contractile responses of rat aorta rings. All compounds were effective Ca1.2 channel blockers, positioning in the α subunit region where standard blockers bind. Among the four newly synthesized morin derivatives, the penta-acetylated morin-1 was the most efficacious Ca antagonist, presenting a vasorelaxant profile superior to that of the parent compound and, contrary to morin, antagonized also the release of Ca from the sarcoplasmic reticulum; surprisingly, it also stimulated K1.1 channel current. Computational analysis demonstrated that morin-1 bound close to the K1.1 channel S6 segment. In conclusion, these findings open a new avenue for the synthesis of valuable multi-functional, vasorelaxant morin derivatives capable to target several pathways underpinning the pathogenesis of hypertension.
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http://dx.doi.org/10.1016/j.bcp.2021.114429DOI Listing
March 2021

Suppressing effect of the novel positive allosteric modulator of the GABA receptor, COR659, on locomotor hyperactivity induced by different drugs of abuse.

Behav Brain Res 2021 02 9;400:113045. Epub 2020 Dec 9.

Neuroscience Institute, Section of Cagliari, National Research Council of Italy, Monserrato, CA, I-09042, Italy. Electronic address:

COR659 is a recently synthesized positive allosteric modulator (PAM) of the GABA receptor. Similarly to all GABA PAMs tested to date, COR659 has been reported to suppress different alcohol-related behaviors in rodents. The present study was designed to assess whether the anti-addictive properties of COR659 extend to drugs of abuse other than alcohol. Specifically, it investigated the effect of COR659 on cocaine-, amphetamine-, nicotine-, and morphine-induced locomotor hyperactivity in mice. To this aim, independent groups of CD1 mice were acutely pretreated with COR659 (0, 10, and 20 mg/kg; i.p.), then acutely treated with cocaine (0 and 10 mg/kg, s.c.), amphetamine (0 and 5 mg/kg; s.c.), nicotine (0 and 0.05 mg/kg; s.c.), or morphine (0 and 20 mg/kg; s.c.), and finally exposed for 60 min to a photocell-equipped motility cage. When given alone, both doses of COR659 were ineffective on spontaneous locomotor activity. Pretreatment with COR659 reduced, or even suppressed, the increase in motility counts induced by cocaine, amphetamine, nicotine, and morphine. Since locomotor hyperactivity is an attribute common to drugs of abuse, the results of the present study constitute the first line of evidence on the extension of the preclinical, anti-addictive profile of COR659 to cocaine, amphetamine, nicotine, and morphine.
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http://dx.doi.org/10.1016/j.bbr.2020.113045DOI Listing
February 2021

Design, synthesis and pharmacological evaluation of ester-based quercetin derivatives as selective vascular K1.1 channel stimulators.

Bioorg Chem 2020 12 22;105:104404. Epub 2020 Oct 22.

Department of Pharmacy, Health and Nutritional Sciences, DoE 2018-2022, University of Calabria, Edificio Polifunzionale, 87036 Rende (CS), Italy.

Quercetin represents one of the most studied dietary flavonoids; it exerts a panel of pharmacological activities particularly on the cardiovascular system. Stimulation of vascular K1.1 channels contributes to its vasorelaxant activity, which is, however, counteracted in part by its concomitant stimulation of Ca1.2 channels. Therefore, several quercetin hybrid derivatives were designed and synthesized to produce a more selective K1.1 channel stimulator, then assessed both in silico and in vitro. All the derivatives interacted with the K1.1 channel with similar binding energy values. Among the selected derivatives, 1E was a weak vasodilator, though displaying an interesting Ca1.2 channel blocking activity. The lipoyl derivatives 1F and 3F, though showing pharmacological and electrophysiological features similar to those of quercetin, seemed to be more effective as K1.1 channel stimulators as compared to the parent compound. The strategy pursued demonstrated how different chemical substituents on the quercetin core can change/invert its effect on Ca1.2 channels or enhance its K1.1 channel stimulatory activity, thus opening new avenues for the synthesis of efficacious vasorelaxant quercetin hybrids.
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http://dx.doi.org/10.1016/j.bioorg.2020.104404DOI Listing
December 2020

Design, Synthesis and In Vitro Experimental Validation of Novel TRPV4 Antagonists Inspired by Labdane Diterpenes.

Mar Drugs 2020 Oct 18;18(10). Epub 2020 Oct 18.

Endocannabinoid Research Group (ERG), Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.

Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents "natural libraries" of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient receptor potential channel subfamily V member 4 (TRPV4) channel has recently emerged as a pharmacological target for several respiratory diseases, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inspired by the labdane-like bicyclic core, a series of homodrimane-derived esters and amides was designed and synthesized by modifying the flexible tail in position 1 of (+)-sclareolide, an oxidized derivative of the bioactive labdane-type diterpene sclareol. The potency and selectivity towards rTRPV4 and hTRPV1 receptors were assessed by calcium influx cellular assays. Molecular determinants critical for eliciting TRPV4 antagonism were identified by structure-activity relationships. Among the selective TRPV4 antagonists identified, compound was the most active with an IC of 5.3 μM. This study represents the first report of semisynthetic homodrimane TRPV4 antagonists, selective over TRPV1, and potentially useful as pharmacological tools for the development of novel TRPV4 channel modulators.
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http://dx.doi.org/10.3390/md18100519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594054PMC
October 2020

The GABA receptor positive allosteric modulator COR659: In vitro metabolism, in vivo pharmacokinetics in rats, synthesis and pharmacological characterization of metabolically protected derivatives.

Eur J Pharm Sci 2020 Dec 12;155:105544. Epub 2020 Sep 12.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, 53100 Siena, Italy. Electronic address:

We report an in vitro phase I metabolism study on COR659 (1), a 2-acylaminothiophene derivative able to suppress alcohol and chocolate self-administration in rats, likely via positive allosteric modulation of the GABA receptor and antagonism/inverse agonism at the cannabinoid CB receptor. Given the identification of the methyl ester group at C-3 of the thiophene ring as a metabolic soft spot, we also report the chemical optimization project aimed to balance metabolic stability with in vitro and in vivo potency on a set of 3-substituted COR659 analogues. High performance liquid chromatography coupled to tandem and high resolution mass spectrometry was employed for the characterization of in vitro metabolism and in vivo pharmacokinetics of COR659 in rats. In vitro [S]GTPγS binding assays on stimulated GABA and CB receptors, in combination with alcohol and chocolate self-administration experiments in rats, were employed to assess the pharmacological profile of this novel set of analogues, using COR659 as reference compound. Eight metabolites of COR659 were discovered in liver microsomal incubates; two of them (M1, M2) were identified by comparison with synthetic reference standards. M2, oxidation product of methyl group at C-5 of the thiophene ring, was a major metabolite in vitro, but showed a low systemic exposure in vivo. M1, cleavage product of the methyl ester group at C-3, revealed in vitro an unusual mechanism of metabolism by a NADPH-dependent route and, in vivo, it maintained high and persistent levels in plasma, which could represent a potential pharmacokinetic and toxicological issue. In the novel set of COR659 analogues, those bearing branched alkyl substituents on the ester group, showed an improved in vitro metabolic stability (2-4), had an in vitro GABA PAM (2-4) and/or CB partial agonist/antagonist profile (2-3) and maintained the ability to reduce alcohol (2-4) and/or chocolate (4) self-administration in rats. Both PK and PD data ruled out any involvement of metabolite M1 in the in vivo potency of COR659 and 4. The present results, therefore, highlight the importance to design and synthesize novel compounds endowed with the dual activity profile and devoid of metabolic liabilities.
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http://dx.doi.org/10.1016/j.ejps.2020.105544DOI Listing
December 2020

Cytotoxic Effects of Cannabinoids on Human HT-29 Colorectal Adenocarcinoma Cells: Different Mechanisms of THC, CBD, and CB83.

Int J Mol Sci 2020 Aug 1;21(15). Epub 2020 Aug 1.

Department of Medical and Surgical Sciences and Neurosciences, University of Siena, 53100 Siena, Italy.

In this study, we investigated the effects of exposition to IC dose for 24 h of a new synthetic cannabinoid (CB83) and of phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on HT-29 colorectal carcinoma cells. Cell viability and proliferative activity evaluated using the MTT, lactate dehydrogenase (LDH), and CyQUANT assays showed that cell viability was significantly affected when CB83, THC, and CBD were administered to cells. The results obtained showed that the reduced glutathione/oxidized glutathione ratio was significantly reduced in the cells exposed to CBD and significantly increased in the cells treated with the CB83 when compared to the controls. CBD treatment causes a significant increase in malondialdehyde content. The catalase activity was significantly reduced in HT-29 cells after incubation with CB83, THC, and CBD. The activities of glutathione reductase and glutathione peroxidase were significantly increased in cells exposed to THC and significantly decreased in those treated with CBD. The ascorbic acid content was significantly reduced in cells exposed to CB83, THC, and CBD. The ultrastructural investigation by TEM highlighted a significantly increased percentage of cells apoptotic and necrotic after CB83 exposition. The Annexin V-Propidium Iodide assay showed a significantly increased percentage of cells apoptotic after CB83 exposition and necrotic cells after CBD and THC exposition. Our results proved that only CBD induced oxidative stress in HT-29 colorectal carcinoma cells via CB receptor-independent mechanisms and that CB83 caused a mainly CB2 receptor-mediated antiproliferative effect comparable to 5-Fuorouracil, which is still the mainstay drug in protocols for colorectal cancer.
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http://dx.doi.org/10.3390/ijms21155533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432098PMC
August 2020

Structure optimization of positive allosteric modulators of GABA receptors led to the unexpected discovery of antagonists/potential negative allosteric modulators.

Bioorg Med Chem Lett 2020 09 28;30(18):127443. Epub 2020 Jul 28.

Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, I-53100 Siena, SI, Italy.

Positive allosteric modulators (PAMs) of GABA receptor represent an interesting alternative to receptor agonists such as baclofen, as they act on the receptor in a more physiological way and thus are devoid of the side effects typically exerted by the agonists. Based on our interest in the identification of new GABA receptor PAMs, we followed a merging approach to design new chemotypes starting from selected active compounds, such as GS39783, rac-BHFF, and BHF177, and we ended up with the synthesis of four different classes of compounds. The new compounds were tested alone or in the presence of 10 µM GABA using [S]GTPγS binding assay to assess their functionality at the receptor. Unexpectedly, a number of them significantly inhibited GABA-stimulated GTPγS binding thus revealing a functional switch with respect to the prototype molecules. Further studies on selected compounds will clarify if they act as negative modulators of the receptor or, instead, as antagonists at the orthosteric binding site.
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http://dx.doi.org/10.1016/j.bmcl.2020.127443DOI Listing
September 2020

Computational drug repurposing for the identification of SARS-CoV-2 main protease inhibitors.

J Biomol Struct Dyn 2021 10 24;39(16):6242-6248. Epub 2020 Jul 24.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.

Accepted 7 July 2020ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the known COVID-19 disease. Since currently no definitive therapies or vaccines for the SARS-CoV-2 virus are available, there is an urgent need to identify effective drugs against SARS-CoV-2 infection. One of the best-known targets available is the main protease of this virus, crucial for the processing of polyproteins codified by viral RNA. In this work, we used a computational virtual screening procedure for the repurposing of commercial drugs available in the DrugBank database as inhibitors of the SARS-CoV-2 main protease. Molecular docking calculations and molecular dynamics (MD) simulations have been applied. The computational model was validated through a self-docking procedure. The screening procedure highlighted five interesting drugs that showed a comparable or higher docking score compared to the crystallographic compound and maintained the protein binding during the MD runs. Amongst these drugs, Ritonavir has been used in clinical trials with patients affected by COVID-19 and Nelfinavir showed anti-SARS-CoV-2 activity. The five identified drugs could be evaluated experimentally as inhibitors of the SARS-CoV-2 main protease in view of a possible COVID-19 treatment. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1796805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441760PMC
October 2021

Design, Synthesis, and Physicochemical and Pharmacological Profiling of 7-Hydroxy-5-oxopyrazolo[4,3-]pyridine-6-carboxamide Derivatives with Antiosteoarthritic Activity In Vivo.

J Med Chem 2020 07 22;63(13):7369-7391. Epub 2020 Jun 22.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.

The hallmark of joint diseases, such as osteoarthritis (OA), is pain, originating from both inflammatory and neuropathic components, and compounds able to modulate the signal transduction pathways of the cannabinoid type-2 receptor (CB2R) can represent a helpful option in the treatment of OA. In this perspective, a set of 18 cannabinoid type-2 receptor (CB2R) ligands was developed based on an unprecedented structure. With the aim of improving the physicochemical properties of previously reported 4-hydroxy-2-quinolone-3-carboxamides, a structural optimization program led to the discovery of isosteric 7-hydroxy-5-oxopyrazolo[4,3-]pyridine-6-carboxamide derivatives. These new compounds are endowed with high affinity for the CB2R and moderate to good selectivity over the cannabinoid type-1 receptor (CB1R), associated with good physicochemical characteristics. As to the functional activity at the CB2R, compounds able to act either as agonists or as inverse agonists/antagonists were discovered. Among them, compound emerged as a potent CB2R agonist able to reduce pain in rats carrying OA induced by injection of monoiodoacetic acid (MIA).
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http://dx.doi.org/10.1021/acs.jmedchem.0c00595DOI Listing
July 2020

Screen of Unfocused Libraries Identified Compounds with Direct or Synergistic Antibacterial Activity.

ACS Med Chem Lett 2020 May 6;11(5):899-905. Epub 2020 Mar 6.

Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena, Viale Bracci 16, 53100 Siena, Italy.

Antibiotic resistance is an increasingly important global public health issue, as major opportunistic pathogens are evolving toward multidrug- and pan-drug resistance phenotypes. New antibiotics are thus needed to maintain our ability to treat bacterial infections. According to the WHO, carbapenem-resistant , , and are the most critical targets for the development of new antibacterial drugs. An automated phenotypic screen was implemented to screen 634 synthetic compounds obtained in-house for both their direct-acting and synergistic activity. Fourteen percent and 10% of the compounds showed growth inhibition against tested Gram-positive and Gram-negative bacteria, respectively. The most active direct-acting compounds showed a broad-spectrum antibacterial activity, including on some multidrug-resistant clinical isolates. In addition, 47 compounds were identified for their ability to potentiate the activity of other antibiotics. Compounds of three different scaffolds (2-quinolones, phenols, and pyrazoles) showed a strong potentiation of colistin, some being able to revert colistin resistance in .
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http://dx.doi.org/10.1021/acsmedchemlett.9b00674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236257PMC
May 2020

Synthetic bioactive olivetol-related amides: The influence of the phenolic group in cannabinoid receptor activity.

Bioorg Med Chem 2020 06 20;28(11):115513. Epub 2020 Apr 20.

Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy.

Focusing on the importance of the free phenolic hydroxyl moiety, a family of 23 alkylresorcinol-based compounds were developed and evaluated for their cannabinoid receptor binding properties. The non-symmetrical hexylresorcinol derivative 29 turned out to be a CB2-selective competitive antagonist/inverse agonist endowed with good potency. Both the olivetol- and 5-(2-methyloctan-2-yl)resorcinol-based derivatives 23 and 24 exhibited a significant antinociceptive activity. Interestingly, compound 24 proved to be able to activate both cannabinoid and TRPV1 receptors. Even if cannabinoid receptor subtype selectivity remained a goal only partially achieved, results confirm the validity of the alkylresorcinol nucleus as skeleton for the identification of potent cannabinoid receptor modulators.
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http://dx.doi.org/10.1016/j.bmc.2020.115513DOI Listing
June 2020

3-Amino-alkylated indoles: unexplored green products acting as anti-inflammatory agents.

Future Med Chem 2020 01 11;12(1):5-17. Epub 2019 Nov 11.

Department of Pharmacy, Health & Nutritional Sciences2, University of Calabria, 87036 Arcavacata di Rende (CS), Italy.

Over the years, indole has proved to be a versatile scaffold for the design of molecules acting as anti-inflammatory agents. A small library of 3-amino-alkylated indoles has been obtained by an optimized Mannich green approach. The anti-inflammatory activity of the new 3-amino-alkylated indoles, GLYC 0-10, was evaluated in RAW 264.7 macrophages. The anti-inflammatory activity of the new 3-amino-alkylated indoles, GLYC 0-10, was evaluatedn and, among them, GLYC 4, 5 and 9 displayed the greatest inhibitory effects on nitric oxide production, with IC values of 5.41, 4.22 and 6.3 μM, respectively. Our outcomes, overall, highlight the importance of the indole substitution in the anti-inflammatory activity of these compounds, exerted by acting on the interlinked NF-κB/ERK1/2 pathways.
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http://dx.doi.org/10.4155/fmc-2019-0234DOI Listing
January 2020

Targeting Neuropathic Pain: Pathobiology, Current Treatment and Peptidomimetics as a New Therapeutic Opportunity.

Curr Med Chem 2020 ;27(9):1469-1500

Department of Pharmacy and Health and Nutrition Sciences, University of Calabria, Edificio Polifunzionale, 87026 Rende (CS), Italy.

There is a huge need for pharmaceutical agents for the treatment of chronic Neuropathic Pain (NP), a complex condition where patients can suffer from either hyperalgesia or allodynia originating from central or peripheral nerve injuries. To date, the therapeutic guidelines include the use of tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors and anticonvulsants, beside the use of natural compounds and non-pharmacological options. Unfortunately, these drugs suffer from limited efficacy and serious dose-dependent adverse effects. In the last decades, the heptapeptide SP1-7, the major bioactive metabolite produced by Substance P (SP) cleavage, has been extensively investigated as a potential target for the development of novel peptidomimetic molecules to treat NP. Although the physiological effects of this SP fragment have been studied in detail, the mechanism behind its action is not fully clarified and the target for SP1-7 has not been identified yet. Nevertheless, specific binding sites for the heptapeptide have been found in brain and spinal cord of both mouse and rats. Several Structure-Affinity Relationship (SAR) studies on SP1-7 and some of its synthetic analogues have been carried out aiming to developing more metabolically stable and effective small molecule SP1-7-related amides that could be used as research tools for a better understanding of the SP1-7 system and, in a longer perspective, as potential therapeutic agents for future treatment of NP.
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http://dx.doi.org/10.2174/0929867326666190530121133DOI Listing
May 2020

Anti-addictive properties of COR659 - Additional pharmacological evidence and comparison with a series of novel analogues.

Alcohol 2019 03 17;75:55-66. Epub 2018 May 17.

Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, I-53100, Siena (SI), Italy.

A recent study found that COR659 (methyl 2-[(4-chlorophenyl)carboxamido]-4-ethyl-5-methylthiophene-3-carboxylate) reduced operant alcohol and chocolate self-administration in rats; COR659 also suppressed cue-induced reinstatement of chocolate seeking in rats. COR659 apparently exerts its effects via a composite mechanism, including positive allosteric modulation of the GABA receptor and an action at the cannabinoid CB receptor. The present study investigated whether the reducing effect of COR659 on alcohol and chocolate self-administration was maintained after repeated treatment and if COR659 affected cue-induced reinstatement of alcohol seeking; additionally, it evaluated the ability of 9 structural analogues of COR659 - designed modifying the substituents on the phenylcarboxamido moiety and replacing the thiophene with the pyridine ring - to affect alcohol and chocolate self-administration. Alcohol self-administration experiments employed Sardinian alcohol-preferring (sP) rats trained to lever-respond for alcohol (15% v/v). Chocolate self-administration experiments employed Wistar rats trained to lever-respond for a chocolate solution (5% w/v Nesquik). In the reinstatement experiment, previously extinguished lever-responding for alcohol in sP rats was reinstated by the non-contingent presentation of an alcohol-associated complex of cues. All drugs were tested at the doses of 0, 2.5, 5, and 10 mg/kg (i.p.). 10-Day treatment with COR659 produced a dose-related reduction of both alcohol and chocolate self-administration, with limited loss of efficacy on continuing treatment. Acute COR659 suppressed reinstatement of alcohol seeking. Among the 9 tested analogues, only COR657 (methyl 2-(benzoylamino)-4-ethyl-5-methylthiophene-3-carboxylate) decreased alcohol self-administration similarly to COR659; all other compounds produced modest, or even no, effect on alcohol self-administration. COR659 excluded, no compound altered chocolate self-administration. These results confirm and extend the ability of COR659 to reduce several behaviors motivated by alcohol and palatable food in rats. Comparison of COR659 to its analogues provided disparate results that do not currently allow any conclusive structure-activity relationship to be hypothesized, as their diverse pharmacological profile apparently does not depend on physicochemical properties.
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http://dx.doi.org/10.1016/j.alcohol.2018.05.007DOI Listing
March 2019

Synthesis of novel 2-(1-adamantanylcarboxamido)thiophene derivatives. Selective cannabinoid type 2 (CB2) receptor agonists as potential agents for the treatment of skin inflammatory disease.

Eur J Med Chem 2019 Jan 13;161:239-251. Epub 2018 Oct 13.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy.

A set of CB2R ligands, based on the thiophene scaffold, was synthesized and evaluated in in vitro assays. Compounds 8c-i, k, l, bearing the 3-carboxylate and 2-(adamantan-1-yl)carboxamido groups together with apolar alkyl/aryl substituents at 5-position or at 4- and 5-positions of the thiophene ring possess high CB2R affinity at low nanomolar concentration, good receptor selectivity, and agonistic functional activity. The full agonist 8g, showing the best balance between receptor affinity and selectivity, was tested in vitro in an experimental model of allergic contact dermatitis and proved to be able to block the release of MCP-2 in HaCaT cells at 10 μM concentration.
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http://dx.doi.org/10.1016/j.ejmech.2018.09.070DOI Listing
January 2019

Quercetin/oleic acid-based G-protein-coupled receptor 40 ligands as new insulin secretion modulators.

Future Med Chem 2017 10 24;9(16):1873-1885. Epub 2017 Oct 24.

Dipartimento di Farmacia & Scienze della Salute & della Nutrizione, 87036 Arcavacata di Rende, Cs, Italy.

Aim: Management of Type 2 diabetes mellitus by diet is achievable at the early stage of the disease; patients usually underestimate this approach and an appropriate drug therapy is required.

Results: Starting from quercetin and oleic acid, that have effect on insulin secretion, a small set of hybrid molecules was synthesized. Insulin secretion was evaluated in both in vitro and ex vivo models.  AV1  was able to enhance insulin secretion dose dependently, behaving as a conceivable agonist of G-protein-coupled receptor 40.

Conclusion: AV1 represents an interesting tool that interacts with G-protein-coupled receptor 40. Further studies will be carried out to evaluate the exact binding mode, and also to enlarge the library of these antidiabetic agents. [Formula: see text].
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http://dx.doi.org/10.4155/fmc-2017-0113DOI Listing
October 2017

Suppressing effect of COR659 on alcohol, sucrose, and chocolate self-administration in rats: involvement of the GABA and cannabinoid CB receptors.

Psychopharmacology (Berl) 2017 Sep 24;234(17):2525-2543. Epub 2017 May 24.

Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, 53100, Siena (SI), Italy.

Rationale And Objectives: COR659 [methyl2-(4-chlorophenylcarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate] is a new, positive allosteric modulator (PAM) of the GABA receptor. This study evaluated whether COR659 shared with previously tested GABA PAMs the capacity to reduce alcohol self-administration in rats.

Results: Treatment with non-sedative doses of COR659 (2.5, 5, and 10 mg/kg; i.p.) suppressed lever-responding for alcohol (15% v/v) in Sardinian alcohol-preferring (sP) rats under the fixed ratio (FR) 4 (FR4) and progressive ratio (PR) schedules of reinforcement; COR659 was more potent and effective than the reference GABA PAM, GS39783. Treatment with COR659, but not GS39783, suppressed (a) lever-responding for a sucrose solution (1-3% w/v) in sP rats under the FR4 and PR schedules, (b) lever-responding for a chocolate solution [5% (w/v) Nesquik®] in Wistar rats under the FR10 and PR schedules, and (c) cue-induced reinstatement of chocolate seeking in Wistar rats. Treatment with COR659 was completely ineffective on lever-responding (FR10) for regular food pellets in food-deprived Wistar rats. Pretreatment with the GABA receptor antagonist, SCH50911, partially blocked COR659-induced reduction of alcohol self-administration, being ineffective on reduction of chocolate self-administration. Pretreatment with the cannabinoid CB receptor antagonist, AM4113, fully blocked COR659-induced reduction of chocolate self-administration, being ineffective on reduction of alcohol self-administration.

Conclusions: COR659 might exert its behavioral effects via a composite mechanism: (i) positive allosteric modulation of the GABA receptor, responsible for a large proportion of reduction of alcohol self-administration; (ii) an action at other receptor system(s), including the cannabinoid CB receptor, through which COR659 affects seeking and consumption of highly palatable foods.
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http://dx.doi.org/10.1007/s00213-017-4644-3DOI Listing
September 2017

TRPV1-FAAH-COX: The Couples Game in Pain Treatment.

ChemMedChem 2016 08 31;11(16):1686-94. Epub 2016 May 31.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Polo Scientifico S. Miniato, 53100, Siena, Italy.

Pain is a complex sensation involving the perception and transduction of diverse environmental pain stimuli with cognitive and emotional processing by the central nervous system. It can manifest as acute or chronic pain. Pain is controlled by a series of enzymes and receptors, implicated in a variety of interconnected mechanisms and pathways. In fact, several studies have shown the cannabinoid receptor 1 and the transient receptor potential vanilloid channel 1 to be new players in modulating the sophisticated pain transduction system at the central level. At the peripheral level, the perception of pain involves cyclooxygenases and fatty acid amide hydrolase, as recent studies demonstrate. This Minireview describes the physiological aspects of the receptors and enzymes mentioned above and focuses on the consideration of dual mechanisms as a new therapeutic approach in the treatment of pain.
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http://dx.doi.org/10.1002/cmdc.201600111DOI Listing
August 2016

Design and Synthesis of New Transient Receptor Potential Vanilloid Type-1 (TRPV1) Channel Modulators: Identification, Molecular Modeling Analysis, and Pharmacological Characterization of the N-(4-Hydroxy-3-methoxybenzyl)-4-(thiophen-2-yl)butanamide, a Small Molecule Endowed with Agonist TRPV1 Activity and Protective Effects against Oxidative Stress.

ACS Chem Neurosci 2016 06 22;7(6):737-48. Epub 2016 Mar 22.

Istituto di Chimica Biomolecolare, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche , Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.

4-(Thiophen-2-yl)butanoic acid was identified as a cyclic substitute of the unsaturated alkyl chain of the natural ligand, capsaicin. Accordingly, a new class of amides was synthesized in good yield and high purity and their molecular recognition against the target was investigated by means of docking experiments followed by molecular dynamics simulations, in order to rationalize their geometrical and thermodynamic profiles. The pharmacological properties of these new compounds were expressed as activation (EC50) and desensitization (IC50) potencies. Several compounds were found to activate TRPV1 channels, and in particular, derivatives 1 and 10 behaved as TRPV1 agonists endowed with good efficacy as compared to capsaicin. The most promising compound 1 was also evaluated for its protective role against oxidative stress on keratinocytes and differentiated human neuroblastoma cell lines expressing the TRPV1 receptor as well as for its cytotoxicity and analgesic activity in vivo.
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http://dx.doi.org/10.1021/acschemneuro.5b00333DOI Listing
June 2016

Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 7. Synthesis and Pharmacological Evaluation of 4-Quinolone-3-carboxamides and 4-Hydroxy-2-quinolone-3-carboxamides as High Affinity Cannabinoid Receptor 2 (CB2R) Ligands with Improved Aqueous Solubility.

J Med Chem 2016 Feb 26;59(3):1052-67. Epub 2016 Jan 26.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.

4-Quinolone-3-carboxamide derivatives have long been recognized as potent and selective cannabinoid type-2 receptor (CB2R) ligands. With the aim to improve their physicochemical properties, basically aqueous solubility, two different approaches were followed, entailing the substitution of the alkyl chain with a basic replacement or scaffold modification to 4-hydroxy-2-quinolone structure. According to the first approach, compound 6d was obtained, showing slightly reduced receptor affinity (K(i) = 60 nM) compared to the lead compound 4 (0.8 nM) but greatly enhanced solubility (400-3400 times depending on the pH of the medium). On the other hand, shifting from 4-quinolone to 4-hydroxy-2-quinolone structure enabled the discovery of a novel class of CB2R ligands, such as 7b and 7c, characterized by K(i) < 1 nM and selectivity index [SI = K(i)(CB1R)/K(i)(CB2R)] > 1300. At pH 7.4, compound 7c resulted by 100-fold more soluble than 4.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01559DOI Listing
February 2016

Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist.

Bioorg Med Chem 2014 Sep 12;22(17):4770-83. Epub 2014 Jul 12.

Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.

In our ongoing program aimed at deeply investigating the endocannabinoid system (ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the importance of the carboxamide functionality. Binding studies on CB1 and CB2 receptors, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds behaved as very potent cannabinoid receptor ligands (Ki in the nanomolar range) while, however, none of them was able to inhibit MAGL and/or FAAH. Derivative 11 was a potent CB1 and CB2 ligand, with Ki values similar to WIN 55,212, exhibiting a CB1 and CB2 agonist profile in vitro. In the formalin test of peripheral acute and inflammatory pain in mice, this compound showed a weak and delayed antinociceptive effect against the second phase of the nocifensive response, exhibiting, interestingly, a quite potent transient receptor potential ankyrin type-1 (TRPA1) channel agonist activity. Moreover, derivative 14, characterized by lower affinity but higher CB2 selectivity than 11, proved to behave as a weak CB2 competitive inverse agonist.
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http://dx.doi.org/10.1016/j.bmc.2014.07.006DOI Listing
September 2014

New fluoroquinolones active against fluoroquinolones-resistant Mycobacterium tuberculosis strains.

Tuberculosis (Edinb) 2013 Jul 22;93(4):405-11. Epub 2013 Mar 22.

Dipartimento di Biotecnologie Mediche, Università di Siena, Policlinico Santa Maria alle Scotte, Viale Bracci 1, 53100 Siena, Italy.

A set of 21 new fluoroquinolones bearing an aromatic or heteroaromatic moiety at C-7 and an alkyl group at N-1 were synthesized based on the lead structure of pirfloxacin and tested in vitro against Mycobacterium tuberculosis (M. tuberculosis) H37Rv by MIC determination in liquid medium. Among the synthesized compounds, 1-(tert-butyl)-6-fluoro-7-(4-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2o) and 1-(tert-butyl)-6-fluoro-7-(pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2n) were found to be the most active ones against M. tuberculosis H37Rv with the same MICs of reference compounds ciprofloxacin (CFX) and levofloxacin (LFX). MICs of 2o and 2n were determined for fluoroquinolone-sensitive and fluoroquinolone-resistant M. tuberculosis clinical isolates and 2o was the most active compound with up 4-fold difference of MIC with respect to CFX. The activity of 2o was also tested at the concentration of 16 μg/mL against M. tuberculosis H37Rv in infected murine macrophages. The results showed a 4-fold decrease in viable count of cell-associated mycobacteria with respect to untreated controls after 48 h of drug incubation.
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http://dx.doi.org/10.1016/j.tube.2013.02.017DOI Listing
July 2013

Investigations on the 4-quinolone-3-carboxylic acid motif. 6. Synthesis and pharmacological evaluation of 7-substituted quinolone-3-carboxamide derivatives as high affinity ligands for cannabinoid receptors.

Eur J Med Chem 2012 Dec 3;58:30-43. Epub 2012 Oct 3.

Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.

Within our studies on structure-activity relationships of 4-quinolone-3-carboxamides as cannabinoid ligands, a new series of compounds characterized by a fluoro or phenylthio group at 7-position and different substituents at N1 and carboxamide nitrogen were synthesized and evaluated for their binding ability to cannabinoid type 1 (CB1) and type 2 (CB2) receptors. Most of the compounds showed affinity for one or both cannabinoid receptors at nanomolar concentration, with K(i)(CB1) and K(i)(CB2) values ranging from 2.45 to >10,000 nM and from 0.09 to 957 nM, respectively. The N-(3,4-dichlorobenzyl)amide derivatives 27 and 40 displayed relatively low affinity, but high selectivity towards the CB1 receptor. Compounds 4 and 40, a CB2 and a CB1 ligand, respectively, behaved as partial agonists in the [(35)S]GTPγS assay. They showed very low permeability through (MDCK-MDR1) cells and might, therefore, represent possible lead structures for further optimization in the search for cannabinoid ligands unable to cross the blood-brain barrier.
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http://dx.doi.org/10.1016/j.ejmech.2012.09.035DOI Listing
December 2012

Resorcinol-sn-glycerol derivatives: novel 2-arachidonoylglycerol mimetics endowed with high affinity and selectivity for cannabinoid type 1 receptor.

J Med Chem 2011 Dec 16;54(24):8278-88. Epub 2011 Nov 16.

Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena, Italy.

Since the discovery of the endocannabinoid system, evidence has been progressively accumulating to suggest that 2-arachidonoylglycerol (2-AG) rather than anandamide (AEA) is the endogenous ligand for both cannabinoid (CB) receptors. Moreover, other studies have shown that another lipid molecule, 2-arachidonyl-glycerol ether (2-AGE, noladin ether), which acts as a full agonist at cannabinoid receptors, might occur in tissues. Having previously designed a resorcinol-AEA hybrid model, in this paper we have explored the cannabinoid receptor binding properties, the CB1 functional activity, and the stability to plasma esterases of a novel series of compounds characterized by the conversion of the amide head into the glycerol-ester or glycerol-ether head, typical of 2-AG or the "putative" endocannabinoid 2-AGE, respectively. Glyceryl esters 39 and 41 displayed greater potency for CB1 (Ki in the nanomolar range) than for CB2 receptors plus the potential to be exploited as useful hits for the development of novel 2-AG mimetics.
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http://dx.doi.org/10.1021/jm200529hDOI Listing
December 2011

1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide: an effective scaffold for the design of either CB1 or CB2 receptor ligands.

Eur J Med Chem 2011 Nov 29;46(11):5641-53. Epub 2011 Sep 29.

Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.

New 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as cannabinoid (CB) receptor ligands. Compound 11 (CB(1)K(i) = 2.3 nM, CB(1) SI = 163.6) showed CB(1) receptor affinity and selectivity superior to Rimonabant and AM251. Acute administration of 2mg/kg 11 reduced sucrose, but not regular food, intake in rats. On the other hand, compound 23 (CB(2)K(i) = 0.51 nM, CB(2) SI = 30.0) showed significant affinity and selectivity for the CB(2) receptor. The results presented here show that the 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide may serve as an effective scaffold for the design of either CB(1) or CB(2) receptor ligands.
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http://dx.doi.org/10.1016/j.ejmech.2011.09.037DOI Listing
November 2011

Synthesis and biological evaluation of new N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides as cannabinoid receptor ligands.

Eur J Med Chem 2010 Dec 1;45(12):5878-86. Epub 2010 Oct 1.

Istituto Pasteur--Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.

A series of N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as new ligands of the human recombinant receptor hCB1. n-Alkyl carboxamides brought out different SARs from the branched subgroup. Unsubstituted pyrrole derivatives bearing a tert-alkyl chain at the 3-carboxamide nitrogen showed greater hCB1 receptor affinity than the corresponding unbranched compounds. In particular, the tert-butyl group as a chain terminal moiety strongly improved hCB1 receptor affinity (compound 24: Ki=45.6 nM; 29: Ki=37.5 nM). Acute administration of either compound 12 or 29 resulted in a specific, dose-dependent reduction in food intake in rats. Such results provide an useful basis for the design of new CB1 ligands.
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http://dx.doi.org/10.1016/j.ejmech.2010.09.053DOI Listing
December 2010

The interactions of the 5-HT3 receptor with quipazine-like arylpiperazine ligands: the journey track at the end of the first decade of the third millennium.

Curr Top Med Chem 2010 ;10(5):504-26

Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università di Siena, Via A. Moro, 53100 Siena, Italy.

The 5-HT(3) receptor (5-HT(3)R) occupies a special place among the serotonin receptor subtypes because it has been shown to be a ligand-gated ion channel, which is involved in a number of physiological functions and important pathologies. 5-HT(3)R antagonists have shown an outstanding efficacy in the control of the emesis induced by anticancer chemotherapy and few adverse side-effects, so as to revolutionize the treatment of nausea in cancer patients. This review covers the authors' work performed during the past decade in the development of 5-HT(3)R ligands belonging to the class of arylpiperazine derivatives related to quipazine (quipazine-like arylpiperazines, QLAs) and represents the extension of the review previously published in Current Topics in Medicinal Chemistry in 2002. The discussion is focused mainly on the most significant structure-affinity relationships emerged in the progress of the work and shows how the original ideas have evolved in the recent years.
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http://dx.doi.org/10.2174/156802610791111560DOI Listing
September 2010
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