DOCSLIB.ORG

Potential Antidepressant Activity of Sigma Ligands

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Potential Antidepressant Activity of Sigma Ligands Copyright © 2003 by Institute of Pharmacology Polish Journal of Pharmacology Polish Academy of Sciences Pol. J. Pharmacol., 2003, 55, 923–934 ISSN 1230-6002 REVIEW POTENTIAL ANTIDEPRESSANT ACTIVITY OF SIGMA LIGANDS Gra¿yna Skuza Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland Potential antidepressant activity of sigma ligands. G. SKUZA. Pol. J. Pharmacol., 2003, 55, 923–934. Despite many years’ studies of antidepressant drugs (ADs), their mecha- nism of action still remains unclear. Recently, it has been postulated that sub- stances capable of reducing neurotransmission at the NMDA complex may represent a new class of ADs. Since several ADs have a high affinity for s receptors, the s binding site may be a relevant mechanism in antidepressant action. Moreover, s ligands are able to modulate the activity of the central neurotransmitter systems, including noradrenergic, serotonergic, dopaminer- gic and glutamatergic (NMDA) ones, which are seemingly important for the mechanism of action of known ADs. The existence of at least two different s s s subtypes of receptors, denoted 1 and 2 is now widely accepted. The se- lective agonists of both s receptor subtypes are available at present. In par- s ticular, a potential antidepressant activity of 1 receptor agonists has been postulated, since the antidepressive-like actions of these compounds have been shown in animal models. This article reviews the findings related to po- tential antidepressant activity of new, selective s ligands. Key words: sigma receptors, selective sigma ligands, antidepressant ac- tivity, animal models G. Skuza 3 Introduction Table 1. IC50 values for drugs competing with the [ H]ligands for s and phencyclidine (PCP) receptor binding sites (rat brain membranes) The term sigma (s) receptors was first proposed by Martin et al. [49] to explain, on the basis of in IC50 (nM) vivo experiments, the effects of benzomorphans, Compound (+)-[3H]SKF (+)-[3H]SKF [3H]TCP such as N-allyl-normetazocine (SKF 10,047), pen- 10,047 10,047 tazocine and cyclazocine which induced a charac- + TCP* + haloperidol teristic pattern of stimulation (“canine delirium”), (+)-SKF 10,047 55 320 405 differentiating these compounds from morphine- (–)-SKF 10,047 690 530 820 syndrome and ketocyclazocine- syndrome. Though (+)-3-PPP 45 > 50000 > 50000 s initially the receptors were considered to be Haloperidol 8 > 50000 > 50000 m k a type of opiate receptor (beside and ), later TCP 8330 25 10 studies (using more selective ligands and more pre- PCP 1450 48 66 cise techniques) convincingly demonstrated that Pentazocine 55 1520 3310 this opinion was not true. Further investigations have revealed that levorotatory form of SKF 10,047 * 1-[1-(2-thienyl)cyclohexyl]piperidine. According to [23] binds primarily to m and k opioid receptors, while its dextrorotatory analogue is distinguished by much s higher affinity for s site and considerable affinity affinity for site, binds to PCP receptor to much for phencyclidine (PCP) receptor. For these reasons, lesser extent (5–8 times) [23]. Martin et al. [49], who used (±)-SKF 10,047, ob- s served as well antinociceptive effects (resulting Characteristics and functions of receptor from the interaction with m and k opioid receptors The s receptors have been labeled and visualized mediated by (–)-SKF 10,047) as psychotomimetic with various radioligands using autoradiographic symptoms, believed to be an effect of (+)-SKF procedures. The numerous data demonstrate that s 10,047 binding to PCP receptors, not reversed by receptors are unevenly distributed in many brain an opiate antagonist, naloxone. areas and are quite abundant in various peripheral The lack of the selectivity shown by several tissues (the kidneys, lungs, intestine, muscles, and, compounds, including benzomorphans and PCP most of all, the liver). In the central nervous system, derivatives on the one hand, and similarities in bio- s receptors are concentrated in brainstem areas, chemical and behavioral effects of some s ligands certain limbic structures, some predominantly sen- and PCP on the other, suggested actions via the sory areas and brain regions associated with endo- same receptor site, so-called “s/PCP”. Further re- crine function [24, 55, 94]. sults (including autoradiographic studies using more Binding studies and in vivo or in vitro func- selective radioligands) demonstrated that s and tional bioassays led to the distinction of at least two s s s PCP receptors were distinct sites and their distribu- subpopulations of receptors, termed 1 and 2 [5, tion in brain regions was found to differ [23, 48, 55, 34, 65]. This classification is mostly based on dif- s 66]. ferences in binding of radioligands: 1 receptor is The use of nonselective ligands, including the able to distinguish between spatial isomers, show- prototypic agonist, N-allyl-normetazocine, to char- ing preference for dextrorotatory forms [(+)-penta- acterize s receptors resulted in an accumulation of zocine, (+)-SKF 10,047, dextrometorphan], whereas confusing and conflicting data which made the the levorotatory form of these compounds as well progress in this field more difficult. Table 1 pres- as haloperidol or 1,3-di-o-tolylguanidine (DTG) bind s s s ents differences in affinity of some ligands of and with high affinity also to the 2 receptors.The 1 PCP receptor sites. These data indicate that (+)-SKF sites are particularly concentrated in the hippocam- 10,047 shows 12.5 times higher affinity for s re- pal formation and other limbic areas (involved in ceptor than its levorotatory analogue, whereas both cognition and emotion), thus, they are suggested to forms exhibit the affinity for PCP receptor (dextro- play an important role in etiology and therapy of rotatory form is somewhat more potent) (Tab. 1). psychiatric disorders [13, 35, 36, 52, 94]. On the s On the other hand, pentazocine, having comparable other hand, the highest densities of 2 receptors 924 Pol. J. Pharmacol., 2003, 55, 923–934 POTENTIAL ANTIDEPRESSANT ACTIVITY OF SIGMA LIGANDS were revealed particularly in regions related to mo- Table 2. Affinities of some compounds for s1 and s2 receptor tor functions (e.g. the motor cortex area, cerebel- sites in the rat brain membranes lum) supporting their possible involvement in the modulation of posture and movements induced by Kd or Ki (nM) Compound s ligands [5, 94]. s s s 1 2 However, 2 binding sites are also likely to mo- dulate emotional responses, since Lu 28-179, a new Haloperidol 3.12 ± 0.23 55.0 ± 9.3 s (+)-Pentazocine 4.59 ± 0.26 1,052 ± 30 selective 2 receptor ligand, shows anxiolytic-like effects in mouse and rat black and white two-com- (–)-Pentazocine 7.41 ± 1.65 42.5 ± 1.7 partment box test, the rat social interaction test and DTG 17.9 ± 5.0 22.2 ± 3.5 the Vogel conflict test [71]. (+)-SKF 10,047 19.4 ± 4.6 2680 ± 444 Binding to s receptor is allosterically modu- 1 Progesterone 24.6 ± 6.6 15700 ± 100 lated by phenytoin and sensitive to the modulatory effects of guanosine triphosphate (GTP) and per- Testosteron 49.7 ± 11.7 > 50000 tussis toxin, which suggests its coupling to G pro- (–)-SKF 10,047 84.9 ± 10.7 1100 ± 170 s Dextrometorphan 85.5 ± 8.5 15800 ± 700 teins (Gi/o). It is thought that activation of 1 recep- tor implicates many second messenger cascades, Dizocilpine (MK-801) 47300 ± 3500 73600 ± 3300 including arachidonic acid cascade, protein kinase C translocation, modulation of the phosphorylation According to [56] state of specific proteins in the brain and phosphati- dyl inositol turnover [19, 26, 60, 94]. Moreover, an An electrophysiological in vivo model for studies s interaction between ligands and calcium channels of selective s receptor ligands has been proposed has been suggested [see: 94]. The findings of Brent by Debonnel et al. [2, 12, 13, 59]. Numerous results et al. [7] demonstrated that protein phosphorylation s 2+ from this laboratory demonstrated that several 1 (dependent on extracellular Ca ) may be one of ligands, e.g. (+)-pentazocine, when applied by mi- the important mechanisms through which s ligands croiontophoresis or administered iv at low doses, produce their effects. potentiated the neuronal response to N-methyl-D- The most commonly used selective s receptor 1 aspartate (NMDA) in the CA region of the rat dor- ligand is (+)-pentazocine, although new, more se- 3 sal hippocampus but did not modify kainate- nor lective compounds of this type have been synthe- quisqualate-induced activations. Only a few s li- sized in recent years (e.g. SA4503), while the DTG, s s s gands, including NE-100 (N,N-dipropyl-2-[4-me- mixed 1/ 2 receptor agonist, has been used as 2 receptor ligand or radioligand (in the presence of thoxy-3-(2-phenylethoxy)phenyl]ethylamine) and (+)-pentazocine). As mentioned above, a selective haloperidol, did not modify NMDA-induced firing s receptor ligand, siramesine, has been introduced activity but suppressed the potentiation of NMDA 2 s recently [71, 86]. The s receptor ligands used so response induced by agonists. Thus, they were s s s far showed low selectivity for its two subpopula- denoted antagonists. Similarly to 1 ligands, 2 tions and for other receptors, particularly dopamine agonists also potentiate the NMDA response [12]. s receptors. For instance, haloperidol, a typical neuro- A majority of agonists tested thus far generate s bell-shaped dose-response curves with respect to leptic, shows high affinity particularly for 1 sites s potentiation of NMDA response. It is worth em- and relatively lower for 2 sites. On the other hand, the aforementioned compound DTG binds with phasizing that this dose-response relationship s s seems characteristic of s receptor ligands, and was comparable potency to both 1 and 2 receptor sub- types (Tab. 2). Interestingly, some neurosteroids (e.g.
Load more

Recommended publications
  • A Role for Sigma Receptors in Stimulant Self Administration and Addiction
    Pharmaceuticals 2011, 4, 880-914; doi:10.3390/ph4060880 OPEN ACCESS pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Review A Role for Sigma Receptors in Stimulant Self Administration and Addiction Jonathan L. Katz *, Tsung-Ping Su, Takato Hiranita, Teruo Hayashi, Gianluigi Tanda, Theresa Kopajtic and Shang-Yi Tsai Psychobiology and Cellular Pathobiology Sections, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]. Received: 16 May 2011; in revised form: 11 June 2011 / Accepted: 13 June 2011 / Published: 17 June 2011 Abstract: Sigma1 receptors (σ1Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs.
    [Show full text]
  • Cerebellar Toxicity of Phencyclidine
    The Journal of Neuroscience, March 1995, 75(3): 2097-2108 Cerebellar Toxicity of Phencyclidine Riitta N&kki, Jari Koistinaho, Frank Ft. Sharp, and Stephen M. Sagar Department of Neurology, University of California, and Veterans Affairs Medical Center, San Francisco, California 94121 Phencyclidine (PCP), clizocilpine maleate (MK801), and oth- Phencyclidine (PCP), dizocilpine maleate (MK801), and other er NMDA antagonists are toxic to neurons in the posterior NMDA receptor antagonistshave attracted increasing attention cingulate and retrosplenial cortex. To determine if addition- becauseof their therapeutic potential. These drugs have neuro- al neurons are damaged, the distribution of microglial ac- protective properties in animal studies of focal brain ischemia, tivation and 70 kDa heat shock protein (HSP70) induction where excitotoxicity is proposedto be an important mechanism was studied following the administration of PCP and of neuronal cell death (Dalkara et al., 1990; Martinez-Arizala et MK801 to rats. PCP (10-50 mg/kg) induced microglial ac- al., 1990). Moreover, NMDA antagonists decrease neuronal tivation and neuronal HSP70 mRNA and protein expression damage and dysfunction in other pathological conditions, in- in the posterior cingulate and retrosplenial cortex. In ad- cluding hypoglycemia (Nellgard and Wieloch, 1992) and pro- dition, coronal sections of the cerebellar vermis of PCP (50 longed seizures(Church and Lodge, 1990; Faingold et al., 1993). mg/kg) treated rats contained vertical stripes of activated However, NMDA antagonists are toxic to certain neuronal microglial in the molecular layer. In the sagittal plane, the populations in the brain. Olney et al. (1989) demonstratedthat microglial activation occurred in irregularly shaped patch- the noncompetitive NMDA antagonists,PCP, MK801, and ke- es, suggesting damage to Purkinje cells.
    [Show full text]
  • Gαq-ASSOCIATED SIGNALING PROMOTES NEUROADAPTATION to ETHANOL and WITHDRAWAL-ASSOCIATED HIPPOCAMPAL DAMAGE
    University of Kentucky UKnowledge Theses and Dissertations--Psychology Psychology 2015 Gαq-ASSOCIATED SIGNALING PROMOTES NEUROADAPTATION TO ETHANOL AND WITHDRAWAL-ASSOCIATED HIPPOCAMPAL DAMAGE Anna R. Reynolds Univerity of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Reynolds, Anna R., "Gαq-ASSOCIATED SIGNALING PROMOTES NEUROADAPTATION TO ETHANOL AND WITHDRAWAL-ASSOCIATED HIPPOCAMPAL DAMAGE" (2015). Theses and Dissertations--Psychology. 74. https://uknowledge.uky.edu/psychology_etds/74 This Doctoral Dissertation is brought to you for free and open access by the Psychology at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Psychology by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies.
    [Show full text]
  • Stems for Nonproprietary Drug Names
    USAN STEM LIST STEM DEFINITION EXAMPLES -abine (see -arabine, -citabine) -ac anti-inflammatory agents (acetic acid derivatives) bromfenac dexpemedolac -acetam (see -racetam) -adol or analgesics (mixed opiate receptor agonists/ tazadolene -adol- antagonists) spiradolene levonantradol -adox antibacterials (quinoline dioxide derivatives) carbadox -afenone antiarrhythmics (propafenone derivatives) alprafenone diprafenonex -afil PDE5 inhibitors tadalafil -aj- antiarrhythmics (ajmaline derivatives) lorajmine -aldrate antacid aluminum salts magaldrate -algron alpha1 - and alpha2 - adrenoreceptor agonists dabuzalgron -alol combined alpha and beta blockers labetalol medroxalol -amidis antimyloidotics tafamidis -amivir (see -vir) -ampa ionotropic non-NMDA glutamate receptors (AMPA and/or KA receptors) subgroup: -ampanel antagonists becampanel -ampator modulators forampator -anib angiogenesis inhibitors pegaptanib cediranib 1 subgroup: -siranib siRNA bevasiranib -andr- androgens nandrolone -anserin serotonin 5-HT2 receptor antagonists altanserin tropanserin adatanserin -antel anthelmintics (undefined group) carbantel subgroup: -quantel 2-deoxoparaherquamide A derivatives derquantel -antrone antineoplastics; anthraquinone derivatives pixantrone -apsel P-selectin antagonists torapsel -arabine antineoplastics (arabinofuranosyl derivatives) fazarabine fludarabine aril-, -aril, -aril- antiviral (arildone derivatives) pleconaril arildone fosarilate -arit antirheumatics (lobenzarit type) lobenzarit clobuzarit -arol anticoagulants (dicumarol type) dicumarol
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances
    WHO/PSM/QSM/2006.3 The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances 2006 Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Medicines Policy and Standards The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
    [Show full text]
  • Drug Sequestration in Lysosomes As One of the Mechanisms of Chemoresistance of Cancer Cells and the Possibilities of Its Inhibition
    International Journal of Molecular Sciences Review Drug Sequestration in Lysosomes as One of the Mechanisms of Chemoresistance of Cancer Cells and the Possibilities of Its Inhibition Jan Hrabˇeta 1, Marie Belhajová 1, Hana Šubrtová 2 , Miguel Angel Merlos Rodrigo 2,3 , ZbynˇekHeger 2,3 and Tomáš Eckschlager 1,* 1 Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, CZ-150 06 Prague, Czech Republic; [email protected] (J.H.); [email protected] (M.B.) 2 Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-613 00 Brno, Czech Republic; [email protected] (H.Š.); [email protected] (M.A.M.R.); [email protected] (Z.H.) 3 Central European Institute of Technologies, Brno University of Technology, CZ-612 00 Brno, Czech Republic * Correspondence: [email protected]; Tel.: +420-606-364-730 Received: 26 May 2020; Accepted: 18 June 2020; Published: 20 June 2020 Abstract: Resistance to chemotherapeutics and targeted drugs is one of the main problems in successful cancer therapy. Various mechanisms have been identified to contribute to drug resistance. One of those mechanisms is lysosome-mediated drug resistance. Lysosomes have been shown to trap certain hydrophobic weak base chemotherapeutics, as well as some tyrosine kinase inhibitors, thereby being sequestered away from their intracellular target site. Lysosomal sequestration is in most cases followed by the release of their content from the cell by exocytosis. Lysosomal accumulation of anticancer drugs is caused mainly by ion-trapping, but active transport of certain drugs into lysosomes was also described. Lysosomal low pH, which is necessary for ion-trapping is achieved by the activity of the V-ATPase.
    [Show full text]
  • Sigma,-Binding Site MARKUS HANNER*, FABIAN F
    Proc. Natl. Acad. Sci. USA Vol. 93, pp. 8072-8077, July 1996 Pharmacology Purification, molecular cloning, and expression of the mammalian sigma,-binding site MARKUS HANNER*, FABIAN F. MOEBIUS*t, ASTRID FLANDORFER*, HANS-GUNTHER KNAUS*, JORG STRIESSNIG*, ELLIS KEMPNERt, AND HARTMUT GLOSSMANN* *Institut fur Biochemische Pharmakologie, Universitat Innsbruck, Peter Mayr Strasse 1, A-6020 Innsbruck, Austria; and tNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892 Communicated by James Black, King's College School of Medicine and Dentistry, London, United Kingdom, April 18, 1996 (received for review March 1, 1996) ABSTRACT Sigma-ligands comprise several chemically The verapamil-like calcium-antagonists azidopamil (a pho- unrelated drugs such as haloperidol, pentazocine, and ditolyl- toligand) and emopamil (an antiischemic drug) are also high- guanidine, which bind to a family of low molecular mass affinity sigma-ligands that were previously employed as specific proteins in the endoplasmic reticulum. These so-called sigma- probes to purify and clone a novel drug-binding membrane receptors are believed to mediate various pharmacological protein from liver. This was distinct from the sigma1-binding site, effects of sigma-ligands by as yet unknown mechanisms. Based although it showed substantial pharmacological and biochemical on their opposite enantioselectivity for benzomorphans and similarities with sigma-receptors (26-29). Until now, sigma- different molecular masses, two subtypes are differentiated. ligand studies suffered from the lack of structural information. To We purified the sigma,-binding site as a single 30-kDa protein clarify its primary structure, we purified the protein carrying the from guinea pig liver employing the benzomorphan sigma,-binding site and cloned the corresponding cDNA using (+) [3H]pentazocine and the arylazide (-) [3H]azidopamil as reverse transcriptase-PCR and degenerate oligonucleotides.
    [Show full text]
  • The Lysosomotropic Activity of Hydrophobic Weak Base Drugs Is Mediated Via Their Intercalation Into the Lysosomal Membrane
    cells Article The Lysosomotropic Activity of Hydrophobic Weak Base Drugs is Mediated via Their Intercalation into the Lysosomal Membrane Michal Stark 1, Tomás F. D. Silva 2, Guy Levin 1, Miguel Machuqueiro 2 and Yehuda G. Assaraf 1,* 1 The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel; [email protected] (M.S.); [email protected] (G.L.) 2 BioISI-Biosystems & Integrative Sciences Institute, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal; [email protected] (T.F.D.S.); [email protected] (M.M.) * Correspondence: [email protected] Received: 5 March 2020; Accepted: 20 April 2020; Published: 27 April 2020 Abstract: Lipophilic weak base therapeutic agents, termed lysosomotropic drugs (LDs), undergo marked sequestration and concentration within lysosomes, hence altering lysosomal functions. This lysosomal drug entrapment has been described as luminal drug compartmentalization. Consistent with our recent finding that LDs inflict a pH-dependent membrane fluidization, we herein demonstrate that LDs undergo intercalation and concentration within lysosomal membranes. The latter was revealed experimentally and computationally by (a) confocal microscopy of fluorescent compounds and drugs within lysosomal membranes, and (b) molecular dynamics modeling of the pH-dependent membrane insertion and accumulation of an assortment of LDs, including anticancer drugs. Based on the multiple functions of the lysosome as a central nutrient sensory hub and a degradation center, we discuss the molecular mechanisms underlying the alteration of morphology and impairment of lysosomal functions as consequences of LDs’ intercalation into lysosomes. Our findings bear important implications for drug design, drug induced lysosomal damage, diseases and pertaining therapeutics.
    [Show full text]
  • Pharmacology and Therapeutic Potential of Sigma1 Receptor Ligands E.J
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central 344 Current Neuropharmacology, 2008, 6, 344-366 Pharmacology and Therapeutic Potential of Sigma1 Receptor Ligands E.J. Cobos1,2, J.M. Entrena1, F.R. Nieto1, C.M. Cendán1 and E. Del Pozo1,* 1Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine, and 2Biomedical Research Center, University of Granada, Granada, Spain Abstract: Sigma () receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of receptors, termed 1 and 2. Of these two subtypes, the 1 re- ceptor has been cloned in humans and rodents, and its amino acid sequence shows no homology with other mammalian proteins. Several psychoactive drugs show high to moderate affinity for 1 receptors, including the antipsychotic haloperi- dol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in ad- dition, the anticonvulsant drug phenytoin allosterically modulates 1 receptors. Certain neurosteroids are known to interact with 1 receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in 2+ intracellular Ca signaling. Sigma1 receptors also play a modulatory role in the activity of some ion channels and in sev- eral neurotransmitter systems, mainly in glutamatergic neurotransmission. In accordance with their widespread modula- tory role, 1 receptor ligands have been proposed to be useful in several therapeutic fields such as amnesic and cognitive deficits, depression and anxiety, schizophrenia, analgesia, and against some effects of drugs of abuse (such as cocaine and methamphetamine).
    [Show full text]
  • I Regulations
    23.2.2007 EN Official Journal of the European Union L 56/1 I (Acts adopted under the EC Treaty/Euratom Treaty whose publication is obligatory) REGULATIONS COUNCIL REGULATION (EC) No 129/2007 of 12 February 2007 providing for duty-free treatment for specified pharmaceutical active ingredients bearing an ‘international non-proprietary name’ (INN) from the World Health Organisation and specified products used for the manufacture of finished pharmaceuticals and amending Annex I to Regulation (EEC) No 2658/87 THE COUNCIL OF THE EUROPEAN UNION, (4) In the course of three such reviews it was concluded that a certain number of additional INNs and intermediates used for production and manufacture of finished pharmaceu- ticals should be granted duty-free treatment, that certain of Having regard to the Treaty establishing the European Commu- these intermediates should be transferred to the list of INNs, nity, and in particular Article 133 thereof, and that the list of specified prefixes and suffixes for salts, esters or hydrates of INNs should be expanded. Having regard to the proposal from the Commission, (5) Council Regulation (EEC) No 2658/87 of 23 July 1987 on the tariff and statistical nomenclature and on the Common Customs Tariff (1) established the Combined Nomenclature Whereas: (CN) and set out the conventional duty rates of the Common Customs Tariff. (1) In the course of the Uruguay Round negotiations, the Community and a number of countries agreed that duty- (6) Regulation (EEC) No 2658/87 should therefore be amended free treatment should be granted to pharmaceutical accordingly, products falling within the Harmonised System (HS) Chapter 30 and HS headings 2936, 2937, 2939 and 2941 as well as to designated pharmaceutical active HAS ADOPTED THIS REGULATION: ingredients bearing an ‘international non-proprietary name’ (INN) from the World Health Organisation, specified salts, esters or hydrates of such INNs, and designated inter- Article 1 mediates used for the production and manufacture of finished products.
    [Show full text]
  • Customs Tariff - Schedule
    CUSTOMS TARIFF - SCHEDULE 99 - i Chapter 99 SPECIAL CLASSIFICATION PROVISIONS - COMMERCIAL Notes. 1. The provisions of this Chapter are not subject to the rule of specificity in General Interpretative Rule 3 (a). 2. Goods which may be classified under the provisions of Chapter 99, if also eligible for classification under the provisions of Chapter 98, shall be classified in Chapter 98. 3. Goods may be classified under a tariff item in this Chapter and be entitled to the Most-Favoured-Nation Tariff or a preferential tariff rate of customs duty under this Chapter that applies to those goods according to the tariff treatment applicable to their country of origin only after classification under a tariff item in Chapters 1 to 97 has been determined and the conditions of any Chapter 99 provision and any applicable regulations or orders in relation thereto have been met. 4. The words and expressions used in this Chapter have the same meaning as in Chapters 1 to 97. Issued January 1, 2019 99 - 1 CUSTOMS TARIFF - SCHEDULE Tariff Unit of MFN Applicable SS Description of Goods Item Meas. Tariff Preferential Tariffs 9901.00.00 Articles and materials for use in the manufacture or repair of the Free CCCT, LDCT, GPT, UST, following to be employed in commercial fishing or the commercial MT, MUST, CIAT, CT, harvesting of marine plants: CRT, IT, NT, SLT, PT, COLT, JT, PAT, HNT, Artificial bait; KRT, CEUT, UAT, CPTPT: Free Carapace measures; Cordage, fishing lines (including marlines), rope and twine, of a circumference not exceeding 38 mm; Devices for keeping nets open; Fish hooks; Fishing nets and netting; Jiggers; Line floats; Lobster traps; Lures; Marker buoys of any material excluding wood; Net floats; Scallop drag nets; Spat collectors and collector holders; Swivels.
    [Show full text]