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1.
Bioorg Med Chem Lett ; 74: 128942, 2022 10 15.
Article in English | MEDLINE | ID: mdl-35973549

ABSTRACT

The discovery of a dual MAO-B/SSAO inhibitor PXS-5131 is reported. The compound offers a compact and rigid three-dimensional structure with superior selectivity over MAO-A. Potency and selectivity are linked to both the double bond geometry and stereochemistry of the allylamine moiety, highlighting the importance of optimal set up of these features in the class of amine oxidase inhibitors. PXS-5131 possesses an attractive preclinical pharmacokinetic profile and has anti-inflammatory properties in models of acute inflammation and neuroinflammation.


Subject(s)
Amine Oxidase (Copper-Containing) , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Monoamine Oxidase , Monoamine Oxidase Inhibitors/pharmacology
2.
Cell Calcium ; 104: 102567, 2022 06.
Article in English | MEDLINE | ID: mdl-35231700

ABSTRACT

The cardiac Na+/Ca2+ Exchanger (NCX1) controls Ca2+ extrusion from the cytosol by mediating bidirectional exchange of Na+ for Ca2+, and therefore controls cardiac relaxation. Insulin regulates Ca2+ handling in cardiac tissue through NCX1, however how insulin changes NCX1 activity is poorly understood. Palmitoylation is the only post-translational modification identified to alter NCX1 activity. Here we show that insulin triggers local structural re-arrangements within existing NCX1 dimers by inducing their palmitoylation, thus tunes NCX1 inactivation through a zDHHC5-dependent mechanism in multiple cell types. By activating fatty acid and fatty acyl CoA synthesis insulin promotes palmitoylation of the zDHHC5 active site, which leads to enhanced NCX1 palmitoylation. Our findings represent a new mechanism to regulate the palmitoylation of numerous zDHHC5 substrates.


Subject(s)
Calcium , Lipoylation , Calcium/metabolism , Heart , Insulin/metabolism , Insulin/pharmacology , Lipoylation/physiology , Sodium/metabolism , Sodium-Calcium Exchanger/metabolism
3.
Cell Calcium ; 97: 102408, 2021 Apr 08.
Article in English | MEDLINE | ID: mdl-33873072

ABSTRACT

Catalyzed by zDHHC-PAT enzymes and reversed by thioesterases, protein palmitoylation is the only post-translational modification recognized to regulate the sodium/calcium exchanger NCX1. NCX1 palmitoylation occurs at a single site at position 739 in its large regulatory intracellular loop. An amphipathic ɑ-helix between residues 740-756 is a critical for NCX1 palmitoylation. Given the rich background of the structural elements involving in NCX1 palmitoylation, the molecular basis of NCX1 palmitoylation is still relatively poorly understood. Here we found that (1) the identity of palmitoylation machinery of NCX1 controls its spatial organization within the cell, (2) the NCX1 amphipathic ɑ-helix directly interacts with zDHHC-PATs, (3) NCX1 is still palmitoylated when it is arrested in either Golgi or ER, indicating that NCX1 is a substrate for multiple zDHHC-PATs, (4) the thioesterase APT1 but not APT2 as a part of NCX1-depalmitoylation machinery governs subcellular organization of NCX1, (5) APT1 catalyzes NCX1 depalmitoylation in the Golgi but not in the ER. We also report that NCX2 and NCX3 are dually palmitoylated, with important implications for substrate recognition and enzyme catalysis by zDHHC-PATs. Our results could support new molecular or pharmacological strategies targeting the NCX1 palmitoylation and depalmitoylation machinery.

4.
Cell Rep ; 31(10): 107697, 2020 06 09.
Article in English | MEDLINE | ID: mdl-32521252

ABSTRACT

The transmembrane sodium-calcium (Na-Ca) exchanger 1 (NCX1) regulates cytoplasmic Ca levels by facilitating electrogenic exchange of Ca for Na. Palmitoylation, the only reversible post-translational modification known to modulate NCX1 activity, controls NCX1 inactivation. Here, we show that palmitoylation of NCX1 modifies the structural arrangement of the NCX1 dimer and controls its affinity for lipid-ordered membrane domains. NCX1 palmitoylation occurs dynamically at the cell surface under the control of the enzymes zDHHC5 and APT1. We identify the position of the endogenous exchange inhibitory peptide (XIP) binding site within the NCX1 regulatory intracellular loop and demonstrate that palmitoylation controls the ability of XIP to bind this site. We also show that changes in NCX1 palmitoylation change cytosolic Ca. Our results thus demonstrate the broad molecular consequences of NCX1 palmitoylation and highlight a means to manipulate the inactivation of this ubiquitous ion transporter that could ameliorate pathologies linked to Ca overload via NCX1.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Sodium-Calcium Exchanger/metabolism , Animals , Binding Sites , Calcium/metabolism , HEK293 Cells , Humans , Ion Transport , Lipoylation , Protein Domains , Protein Processing, Post-Translational , Rabbits , Rats , Rats, Wistar , Sodium-Calcium Exchanger/genetics
5.
Bioorg Med Chem Lett ; 22(7): 2560-4, 2012 Apr 01.
Article in English | MEDLINE | ID: mdl-22381048

ABSTRACT

A series of substituted 4-arylpiperidines and a smaller family of 4-aryl-1,2,3,6-tetrahydropyridines were synthesized and their biological activity at the 5-HT(2C) receptor studied to determine whether either series showed noteworthy agonist activity. Structure-activity relationships were developed from the performed receptor binding assays and functional studies, and the results of the analysis are presented herein.


Subject(s)
Appetite Depressants/chemical synthesis , Piperidines/chemical synthesis , Pyridines/chemical synthesis , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Animals , Appetite Depressants/pharmacology , Calcium/metabolism , Ergolines/pharmacology , Humans , Kinetics , Piperidines/pharmacology , Protein Binding , Pyridines/pharmacology , Radioligand Assay , Receptor, Serotonin, 5-HT2C/chemistry , Serotonin 5-HT2 Receptor Agonists/pharmacology , Serotonin Antagonists/pharmacology , Stereoisomerism , Structure-Activity Relationship
6.
Bioorg Med Chem ; 19(11): 3549-57, 2011 Jun 01.
Article in English | MEDLINE | ID: mdl-21550811

ABSTRACT

As part of a programme investigating antibacterial cyclic macrocycles containing a cationic amino acid with an internal aromatic hydrophobic scaffold, we previously reported a macrocycle anchored at the 3,3'-positions of a 1,1'-binaphthyl unit. This was prepared via key intermediates containing an internal allylglycine and an allyl-substituted binaphthyl unit for a subsequent ring-closing metathesis reaction. This paper presents some structure-activity relationship studies with additional macrocycles based on this lead compound against Staphylococcus aureus together with the antibacterial activity of two related acyclic compounds.


Subject(s)
Amino Acids/chemistry , Anti-Bacterial Agents/chemical synthesis , Macrocyclic Compounds/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cations/chemistry , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Stereoisomerism , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 21(6): 1644-8, 2011 Mar 15.
Article in English | MEDLINE | ID: mdl-21333535

ABSTRACT

The discovery of a small molecule non-nucleoside inhibitor of Hepatitis B Virus is described. During our work on conocurvone derived naphthoquinone 'trimers' for the treatment of HIV, we discovered a potent inhibitor 9 of Hepatitis B Virus in an antiviral screen. During attempts to resynthesis 9 for proof of concept studies, we altered the synthesis in order to attempt to reduced side reactions and difficult to remove by-products. As a result we discovered a small molecule 19 that also was a potent inhibitor of HBV. Importantly, this small molecule inhibitor of Hepatitis B Virus is also an inhibitor of Hepatitis B Virus resistant to 3TC, a bench mark of nucleoside analogues active in the treatment of Hepatitis B Virus. The development of 19 as an agent to treat HBV infections is discussed.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepatitis B virus/drug effects , Animals , Drug Discovery
8.
Bioorg Med Chem ; 18(17): 6442-50, 2010 Sep 01.
Article in English | MEDLINE | ID: mdl-20685126

ABSTRACT

The synthesis of a new series of conocurvone analogues is presented that explores the importance of the pyran rings of conocurvone, their degree of unsaturation as well as the role of alkoxy functionalities as pyran ring replacements, for the inhibition of the HIV-1 integrase (IN) enzyme. Difficulties in synthesising a trimeric naphthoquinone where the central quinone bears a peri-dihydropyran ring was attributed to distortion of the electrophilic dihaloquinone successfully utilised in the past. Increased electron density could also be a factor in reducing reactivity. The desired central dihydropyran bearing trimeric naphthoquinone was successfully synthesised by using a more reactive bromo-tosyloxyquinone intermediate. A maleimide derivative, where the central quinone between the pendant hydroxyquinones was replaced, was successfully synthesised and although it exhibited comparable enzyme inhibitory activity it had negligible HIV inhibitory cellular activity. Compounds were assessed for activity in both in vitro assays using purified recombinant HIV-1 IN and demonstrated superior or comparable activity to conocurvone derivatives previously reported.


Subject(s)
Anti-HIV Agents/chemical synthesis , Naphthoquinones/chemical synthesis , Naphthoquinones/pharmacology , Animals , Anti-HIV Agents/pharmacology , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacology , HIV-1/enzymology , Humans , Rats
9.
Eur J Med Chem ; 43(3): 513-39, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17582659

ABSTRACT

An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB(1) agonists. It is hoped that compounds of this type will have clinical utility in pain control, and cerebral ischaemia following stroke or traumatic head injury. We report here medicinal chemistry studies directed towards the investigation of a series of 1-substituted-indole-3-oxadiazoles as potential CB(1) agonists.


Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Cannabinoids/metabolism , Indoles/chemical synthesis , Indoles/pharmacology , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Receptor, Cannabinoid, CB1/agonists , Analgesics/chemistry , Analgesics/metabolism , Animals , Binding Sites , Drug Design , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Indoles/chemistry , Indoles/metabolism , Inhibitory Concentration 50 , Mice , Oxadiazoles/chemistry , Oxadiazoles/metabolism , Rats , Receptor, Cannabinoid, CB1/chemistry , Receptor, Cannabinoid, CB1/metabolism , Substrate Specificity
10.
Nat Med ; 11(5): 507-14, 2005 May.
Article in English | MEDLINE | ID: mdl-15834429

ABSTRACT

Platelet activation at sites of vascular injury is essential for the arrest of bleeding; however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances (high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(3) adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K p110beta as an important new target for antithrombotic therapy.


Subject(s)
Arteries/pathology , Phosphatidylinositol 3-Kinases/metabolism , Platelet Adhesiveness/physiology , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Signal Transduction/physiology , Thrombosis/metabolism , Animals , Bleeding Time , Blood Platelets/metabolism , Flow Cytometry , Isoenzymes/metabolism , Mice , Mice, Knockout , Phosphoinositide-3 Kinase Inhibitors , Rheology , Serotonin/metabolism , Thrombosis/pathology , rap GTP-Binding Proteins/metabolism
11.
Pharmacol Biochem Behav ; 80(1): 9-26, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15652376

ABSTRACT

A new mechanism has been recently proposed, whereby melatonin may participate in the ongoing process of neuronal degeneration in models of neurodegenerative disorders, such as Parkinson's disease (PD). Antagonism of the melatonin receptor in rats using constant light or pinealectomy induced recovery and reduced the mortality typically associated with dopamine (DA) degeneration. In additional studies, employing ML-23 in the 6-OHDA-treated rat, remission from experimental PD was achieved using this drug in a post 6-OHDA treatment regime. To permit the further assessment of ML-23 as a potential clinical candidate for the treatment of PD, the present study was undertaken to determine the efficacy of ML-23 in the 1-methyl-4-phenyl, 1,2,3,6 tetrahydropyridine (MPTP) model in the common marmoset. ML-23 was administered orally in a dose of 3 mg/kg twice daily to half of the animals, while the other half received vehicle only, in a blinded protocol, for 56 days. The effects of the treatment on positive and negative features of MPTP-induced PD were assessed, including horizontal and vertical movement, head checking, general behaviour and Parkinsonian condition, raisin board performance, the ability to remove a foot label, palatable and dry food intake, water consumption, bradykinaesia, and the positive symptoms of tremor, obstinate progression, and agitation. On all parameters, ML-23 produced a significant remission from MPTP-induced Parkinsonism, and this effect did not abate when ML-23 treatment was withdrawn. In a further pilot study involving a crossover of two animals, one animal treated previously with MPTP plus vehicle showed some remission of negative and positive features, although ML-23 treatment was not commenced until 8 weeks post-MPTP. Conversely, a recurrence of Parkinsonian signs was not observed when ML-23 treatment was withdrawn and substituted with oral vehicle. Dopamine transporter was severely impaired in all marmosets treated with ML-23 or vehicle for the duration of the study. These results suggest that a novel mechanism involving melatonin is involved in the primary aetiology of the chronic aspects of PD, and such a mechanism is not related to the antioxidative function of this hormone. From these preliminary results, it is concluded that ML-23 and other melatonin analogues have an important role to play in the treatment and clinical management of Parkinson's disease.


Subject(s)
5-Methoxytryptamine/analogs & derivatives , 5-Methoxytryptamine/therapeutic use , Melatonin/analogs & derivatives , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/physiopathology , Recovery of Function/drug effects , 5-Methoxytryptamine/pharmacology , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Callithrix , Cross-Over Studies , Eating/drug effects , Eating/physiology , Male , Melatonin/antagonists & inhibitors , Reaction Time/drug effects , Reaction Time/physiology , Recovery of Function/physiology
12.
Pharmacol Biochem Behav ; 79(3): 413-29, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15582013

ABSTRACT

Over the past 10 years, there has been a resurgence of interest in examining the role of melatonin in health and disease. While the brunt of research in this area has portrayed melatonin in a favorable light, there is a growing body of evidence suggesting that melatonin may possess adverse effects contributing to the development of various neuropsychiatric disease states. In preclinical models of Parkinson's disease (PD), melatonin has been shown to enhance the severity of this condition while its antagonism, using constant light or pinealectomy, facilitates recovery. To test this hypothesis further, the present study employed the melatonin analogues ML-23 and S-20928 in a post-6-OHDA injection regime to determine whether they may have a favorable effect on the symptoms of this more chronic model of PD. When ML-23 was injected I.P. in a dose of 3 mg/kg twice daily for 3.5 days after 6-OHDA, significant improvement in motor function and regulatory deficits was observed. Similarly, the injection of S-20928 in a 1 mg/kg dose (I.P.), in the same regimen, facilitated modest improvement in motor function and regulatory deficits while the larger dose enhanced the severity of behavioural deficits and produced severe side effects causing deterioration in condition during the course of drug administration. ML-23 administration totally abolished the 6-OHDA-induced mortality, which accompanies dopamine (DA) degeneration, while S-20928 had no effect on this parameter. These results suggest that some melatonin analogues can aid in recovery from DA depleting lesions after DA degeneration has commenced and the recovery is not attributable to the antioxidative properties of this hormone. While the exact mechanism by which ML-23 and S-20928 are exerting their therapeutic effect is unclear, it is possible that antagonism of melatonin receptors may play some role and this should be considered when assessing the potential of melatonin analogues for treatment of human neuropsychiatric disorders.


Subject(s)
5-Methoxytryptamine/analogs & derivatives , 5-Methoxytryptamine/therapeutic use , Melatonin/analogs & derivatives , Naphthalenes/therapeutic use , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/physiopathology , Receptors, Melatonin/antagonists & inhibitors , 5-Methoxytryptamine/pharmacology , Animals , Male , Naphthalenes/pharmacology , Oxidopamine/toxicity , Rats , Rats, Sprague-Dawley , Receptors, Melatonin/physiology , Recovery of Function/drug effects , Recovery of Function/physiology
13.
Pain ; 96(1-2): 119-27, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11932068

ABSTRACT

N-type calcium channels modulate the release of key pro-nociceptive neurotransmitters such as glutamate and substance P (SP) in the central nervous system. Considerable research interest has focused on the therapeutic potential of the peptidic omega-conopeptides, GVIA and MVIIA as novel analgesic agents, due to their potent inhibition of N-type calcium channels. Recently, the novel peptidic N-type calcium channel blocker, AM336, was isolated from the venom of the cone snail, Conus catus. Thus, the aims of this study were to (i) document the antinociceptive effects of AM336 (also known as CVID) relative to MVIIA following intrathecal (i.t.) bolus dosing in rats with adjuvant-induced chronic inflammatory pain of the right hindpaw and to (ii) quantify the inhibitory effects of AM336 relative to MVIIA on K+-evoked SP release from slices of rat spinal cord. Both AM336 and MVIIA inhibited the K+-evoked release of the pro-nociceptive neurotransmitter, SP, from rat spinal cord slices in a concentration-dependent manner (EC50 values=21.1 and 62.9 nM, respectively), consistent with the antinociceptive actions of omega-conopeptides. Following acute i.t. dosing, AM336 evoked dose-dependent antinociception (ED50 approximately 0.110 nmol) but the doses required to produce side-effects were an order of magnitude larger than the doses required to produce antinociception. For i.t. doses of MVIIA0.07 nmol, produced a dose-dependent decrease in antinociception but the incidence and severity of the side-effects continued to increase for all doses of MVIIA investigated, suggesting that dose-titration with MVIIA in the clinical setting, may be difficult.


Subject(s)
Calcium Channel Blockers/pharmacology , Calcium Channels, N-Type/metabolism , Nociceptors/drug effects , Spinal Cord/metabolism , Substance P/metabolism , Venoms/pharmacology , Animals , Dose-Response Relationship, Drug , Injections, Spinal , Male , Organ Culture Techniques , Pain Threshold/drug effects , Potassium/pharmacology , Rats , Rats, Sprague-Dawley , Specific Pathogen-Free Organisms , Spinal Cord/drug effects , omega-Conotoxins/pharmacology
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