Novel Dual-Acting Hybrids Targeting Type-2 Cannabinoid Receptors and Cholinesterase Activity Show Neuroprotective Effects In Vitro and Amelioration of Cognitive Impairment In Vivo.

Alzheimer's disease (AD) is a neurodegenerative form of dementia characterized by the loss of synapses and a progressive decline in cognitive abilities. Among current treatments for AD, acetylcholinesterase (AChE) inhibitors have efficacy limited to symptom relief, with significant side effects and poor compliance. Pharmacological agents that modulate the activity of type-2 cannabinoid receptors (CB2R) of the endocannabinoid system by activating or blocking them have also been shown to be effective against neuroinflammation.

Anorectic effect of COR659 in a rat model of overeating.

COR659 is a new compound, the action of which is exerted via a dual mechanism: positive allosteric modulation of the GABAB receptor; antagonism or inverse agonism at the cannabinoid CB1 receptor. Recent lines of experimental evidence have indicated that COR659 potently and effectively reduced operant self-administration of and reinstatement of seeking behaviour for a chocolate-flavoured beverage. The present study was designed to assess whether the ability of COR659 to diminish these addictive-like, food-motivated behaviours extended to a rat model of overeating palatable food.

Investigation on Novel 2-Benzylideneindan-1-One-Based Photoswitches with AChE and MAO-B Dual Inhibitory Activity.

The multitarget therapeutic strategy, as opposed to the more traditional 'one disease-one target-one drug', may hold promise in treating multifactorial neurodegenerative syndromes, such as Alzheimer's disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy-2,3-dihydro-1-inden-1-one (), which in the isomeric form (and about tenfold less in the UV-B photo-induced isomer ) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs - with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity.

Systematic Modification of the Substitution Pattern of the 7-Hydroxy-5-oxopyrazolo[4,3-]pyridine-6-carboxamide Scaffold Enabled the Discovery of New Ligands with High Affinity and Selectivity for the Cannabinoid Type 2 Receptor.

Selective ligands of the CB2 receptor are receiving considerable attention due to their potential as therapeutic agents for a variety of diseases. Recently, 7-hydroxy-5-oxopyrazolo[4,3-]pyridine-6-carboxamide derivatives were shown to act at the CB2 receptor either as agonists or as inverse agonists/antagonists in vitro and to have anti-osteoarthritic activity in vivo. In this article, we report the synthesis, pharmacological profile, and molecular modeling of a series of twenty-three new 7-hydroxy-5-oxopyrazolo[4,3-]pyridine-6-carboxamides with the aim of further developing this new class of selective CB2 ligands.

The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 Inhibition.

Neuropathic pain is a chronic disabling condition with a 7-10% of prevalence in the general population that is largely undertreated. Available analgesic therapies are poorly effective and are often accompanied by numerous side effects. Growing evidence indicates cannabinoids are a valuable treatment opportunity for neuropathic pain.

-Guided Rational Drug Design and Synthesis of Novel 4-(Thiophen-2-yl)butanamides as Potent and Selective TRPV1 Agonists.

We describe an -guided rational drug design and the synthesis of the suggested ligands, aimed at improving the TRPV1-ligand binding properties and the potency of -(4-hydroxy-3-methoxybenzyl)-4-(thiophen-2-yl) butanamide , a previously identified TRPV1 agonist. The docking experiments followed by molecular dynamics simulations and thermodynamic analysis led the drug design toward both the introduction of a lipophilic iodine and a flat pyridine/benzene at position 5 of the thiophene nucleus. Most of the synthesized compounds showed high TRPV1 efficacy and potency as well as selectivity.

Reducing effect of intragastrically administered saikosaponin A on alcohol and sucrose self-administration in rats.

Saikosaponin A (SSA) is an active ingredient of the Asian medicinal herb, L. When administered the intraperitoneal (i.p.

Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant .

The diffusion of antibiotic-resistant, Gram-negative, opportunistic pathogens, an increasingly important global public health issue, causes a significant socioeconomic burden. isolates, despite causing a lower number of infections than Enterobacterales, often show multidrug-resistant phenotypes. Carbapenem resistance is also rather common, prompting the WHO to include carbapenem-resistant as a "critical priority" for the discovery and development of new antibacterial agents.

Lipoic/Capsaicin-Related Amides: Synthesis and Biological Characterization of New TRPV1 Agonists Endowed with Protective Properties against Oxidative Stress.

α-Lipoic acid is a sulfur-containing nutrient endowed with pleiotropic actions and a safe biological profile selected to replace the unsaturated alkyl acid of capsaicin with the aim of obtaining lipoic amides potentially active as a TRPV1 ligand and with significant antioxidant properties. Thus, nine compounds were obtained in good yields following a simple synthetic procedure and tested for their functional TRPV1 activity and radical-scavenger activity. The safe biological profile together with the protective effect against hypoxia damage as well as the in vitro antioxidant properties were also evaluated.

Development of tolerance upon repeated administration with the GABA receptor positive allosteric modulator, COR659, on alcohol drinking in rodents.

Recent work has demonstrated that acute administration of the novel positive allosteric modulator of the GABA receptor, COR659, reduces several alcohol-related behaviors in rodents. To assess whether COR659 continues to lessen alcohol intake after repeated administration, a fundamental feature of drugs with therapeutic potential. Male C57BL/6J mice (n = 40) were exposed to daily 2-hour drinking sessions (20% (v/v) alcohol) under the 1-bottle "drinking in the dark" protocol and male Sardinian alcohol-preferring rats (n = 40) were exposed to daily 1-hour drinking sessions under the 2-bottle "alcohol (10%, v/v) vs water" choice regimen.

Design, synthesis and biological evaluation of light-driven on-off multitarget AChE and MAO-B inhibitors.

Neurodegenerative diseases are multifactorial disorders characterized by protein misfolding, oxidative stress, and neuroinflammation, finally resulting in neuronal loss and cognitive dysfunctions. Nowadays, an attractive strategy to improve the classical treatments is the development of multitarget-directed molecules able to synergistically interact with different enzymes and/or receptors. In addition, an interesting tool to refine personalized therapies may arise from the use of bioactive species able to modify their activity as a result of light irradiation.

In Silico Multi-Target Approach Revealed Potential Lead Compounds as Scaffold for the Synthesis of Chemical Analogues Targeting SARS-CoV-2.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease that spreads rapidly in humans. In March 2020, the World Health Organization (WHO) declared a COVID-19 pandemic. Identifying a multi-target-directed ligand approach would open up new opportunities for drug discovery to combat COVID-19.

Reducing effect of the novel positive allosteric modulator of the GABA receptor, COR659, on binge-like alcohol drinking in male mice and rats.

Rationale: Binge drinking (BD) is a widespread drinkingpattern that may contribute to promote the development of alcohol use disorder (AUD). The comprehension of its neurobiological basis and the identification of molecules that may prevent BD are critical. Preclinical studies demonstrated that positive allosteric modulators (PAMs) of the GABA receptor effectively reduced, and occasionally suppressed, the reinforcing and motivational properties of alcohol in rodents, suggesting their potential use as pharmacotherapy for AUD, including BD.

Has a "Chemical Magic" Opened up New Prospects for Glaucoma?

Chemical modification of the prototype CB1R ago-PAM, GAT211, yielded new CB1R allosteric modulators (-)-(,)- and (+)-(,)-, which showed significant bias for CB1R signaling pathways, as supported by docking studies. Compound efficiently lowered elevated intraocular pressure when it is due to an increase in endocannabinoid tone. This article may open new avenues to meet the therapeutic needs presented by glaucoma.

COR758, a negative allosteric modulator of GABA receptors.

Allosteric modulators of G protein coupled receptors (GPCRs), including GABARs (GABARs), are promising therapeutic candidates. While several positive allosteric modulators (PAM) of GABARs have been characterized, only recently the first negative allosteric modulator (NAM) has been described. In the present study, we report the characterization of COR758, which acts as GABAR NAM in rat cortical membranes and CHO cells stably expressing GABARs (CHO-GABA).

Viral Envelope Membrane: A Special Entry Pathway and a Promising Drug Target.

Enveloped viruses belong to a large class of pathogens responsible for multiple serious diseases. Their spread into new territories has been the cause of major epidemics throughout human history, including the Spanish flu in 1918 and the latest COVID-19 pandemic. Thanks to their outer membrane, consisting essentially of host lipids, enveloped viruses are more resistant to enzymes and are also less susceptible to host immune defenses than their naked counterparts.

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

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.

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

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.

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

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.

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

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.

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

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.

Differential Effects of Saikosaponins A, B2, B4, C and D on Alcohol and Chocolate Self-Administration in Rats.

Aims: Treatment with saikosaponin A (SSA)-an ingredient of the medicinal herb, Bupleurum falcatum-has been reported to suppress several addictive-like behaviors, including morphine, cocaine, alcohol and chocolate self-administration in male rats. The aim of this investigation was to investigate whether saikosaponins of B. falcatum other than SSA affect alcohol and chocolate self-administration in rats.

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

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.

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

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.