A Convenient Synthetic Approach and Estimation of Their Affinity at Neuronal Nicotinic
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PRODUCT INFORMATION α-Bungarotoxin (trifluoroacetate salt) Item No. 16385 Synonyms: α-Bgt, α-BTX Peptide Sequence: IVCHTTATSPISAVTCPPGENLCY Ile Val Cys His Thr Thr Ala Thr Ser Pro RKMWCDAFCSSRGKVVELGCAA Ile Ser Ala Val Thr Cys Pro Pro Gly Glu TCPSKKPYEEVTCCSTDKCNPHP KQRPG, trifluoroacetate salt Asn Leu Cys Tyr Arg Lys Met Trp Cys Asp (Modifications: Disulfide bridge between Ala Phe Cys Ser Ser Arg Gly Lys Val Val 3-23, 16-44, 29-33, 48-59, 60-65) Glu Leu Gly Cys Ala Ala Thr Cys Pro Ser MF: C338H529N97O105S11 • XCF3COOH FW: 7,984.2 Lys Lys Pro Tyr Glu Glu Val Thr Cys Cys Supplied as: A solid Ser Thr Asp Lys Cys Asn Pro His Pro Lys Storage: -20°C Gln Arg Pro Gly Stability: ≥2 years • XCF COOH Solubility: Soluble in aqueous buffers 3 Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures α-Bungarotoxin (trifluoroacetate salt) is supplied as a solid. A stock solution may be made by dissolving the α-bungarotoxin (trifluoroacetate salt) in water. The solubility of α-bungarotoxin (trifluoroacetate salt) in water is approximately 1 mg/ml. We do not recommend storing the aqueous solution for more than one day. Description α-Bungarotoxin is a snake venom-derived toxin that irreversibly binds nicotinic acetylcholine receptors (Ki = ~2.5 µM in rat) present in skeletal muscle, blocking action of acetylcholine at the postsynaptic membrane and leading to paralysis.1-3 It has been widely used to characterize activity at the neuromuscular junction, which has numerous applications in neuroscience research.4,5 References 1. -
PRODUCT INFORMATION ABT-594 Item No
PRODUCT INFORMATION ABT-594 Item No. 22822 CAS Registry No.: 203564-54-9 Formal Name: 5-[(2R)-2-azetidinylmethoxy]-2- H chloro-pyridine, monohydrochloride N Synonyms: Ebanicline, Tebanicline O MF: C9H11ClN2O • HCl FW: 235.1 N Purity: ≥95% Cl Supplied as: A solid • HCl Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures ABT-594 is supplied as a solid. A stock solution may be made by dissolving the ABT-594 in the solvent of choice. ABT-594 is soluble in the organic solvent DMSO, which should be purged with an inert gas. Description ABT-594 is a potent agonist of neuronal α4β2 subunit-containing nicotinic acetylcholine receptors 1 (nAChRs; Ki = 37 pM in a radioligand binding assay). It is selective for neuronal nAChRs over neuromuscular α1β1δγ subunit-containing nAChRs (Ki = 10,000 nM), α1B-, α2B-, and α2C-adrenergic receptors (Kis = 890, 597, and 342 nM, respectively), and 70 other receptors, enzymes, and transporters 86 + (Kis = >1,000 nM) in radioligand binding assays. ABT-594 induces [ Rb ] efflux in K177 cells transfected with human neuronal α4β2 subunit-containing nAChRs (EC50 = 140 nM). In vivo, ABT-594 (0.05 and 0.01 mg/kg, s.c.) increases latency to paw withdrawal in a hot-plate test in rats.2 It also induces hypothermia, seizures, and an increase in blood pressure. References 1. Donnelly-Roberts, D.L., Puttfarcken, P.S., Kuntzweiler, T.A., et al. ABT-594 [(R)-5-(2-azetidinylmethoxy)- 2-chloropyridine]: A novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. -
(19) United States (12) Patent Application Publication (10) Pub
US 20130289061A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0289061 A1 Bhide et al. (43) Pub. Date: Oct. 31, 2013 (54) METHODS AND COMPOSITIONS TO Publication Classi?cation PREVENT ADDICTION (51) Int. Cl. (71) Applicant: The General Hospital Corporation, A61K 31/485 (2006-01) Boston’ MA (Us) A61K 31/4458 (2006.01) (52) U.S. Cl. (72) Inventors: Pradeep G. Bhide; Peabody, MA (US); CPC """"" " A61K31/485 (201301); ‘4161223011? Jmm‘“ Zhu’ Ansm’ MA. (Us); USPC ......... .. 514/282; 514/317; 514/654; 514/618; Thomas J. Spencer; Carhsle; MA (US); 514/279 Joseph Biederman; Brookline; MA (Us) (57) ABSTRACT Disclosed herein is a method of reducing or preventing the development of aversion to a CNS stimulant in a subject (21) App1_ NO_; 13/924,815 comprising; administering a therapeutic amount of the neu rological stimulant and administering an antagonist of the kappa opioid receptor; to thereby reduce or prevent the devel - . opment of aversion to the CNS stimulant in the subject. Also (22) Flled' Jun‘ 24’ 2013 disclosed is a method of reducing or preventing the develop ment of addiction to a CNS stimulant in a subj ect; comprising; _ _ administering the CNS stimulant and administering a mu Related U‘s‘ Apphcatlon Data opioid receptor antagonist to thereby reduce or prevent the (63) Continuation of application NO 13/389,959, ?led on development of addiction to the CNS stimulant in the subject. Apt 27’ 2012’ ?led as application NO_ PCT/US2010/ Also disclosed are pharmaceutical compositions comprising 045486 on Aug' 13 2010' a central nervous system stimulant and an opioid receptor ’ antagonist. -
Efforts Towards the Synthesis of Epibatidine By: Marianne Hanna
Efforts Towards the Synthesis of Epibatidine By: Marianne Hanna (Junior-Biochemistry major) Faculty Advisor: Dr. Thomas Montgomery Duquesne University- Bayer School of Natural Sciences 1 Abstract: Epibatidine is a naturally toxic chemical found in the secretion of poison dart frogs. Given its structural similarities to the compound nicotine epibatidine binds strongly to nicotine receptors in the central nervous system (CTS). Epibatidine’s bioactivity arises from its unique geometry which allows it to bind to the α4β2 subunit in the nicotinic receptor. This triggers an analgesic effect without a release of dopamine, differentiating its activity from opioids. Prior efforts towards synthesizing epibatidine and its analogs have involved many steps making them untenable for pharmaceutical use. By using computational and experimental methods to study the mechanism for an interrupted Polonovski [3+2] cycloaddition which will give direct access to the epibatidine core motif. By synthesizing strategic derivatives of epibatidine through this route we will investigate opioid alternatives which lack many of their addictive qualities. Background: Epibatidine is a toxic alkaloid that is isolated from the skin of poison dart tree frog Epipedobates tricolor, secretions from the frog are used by indigenous tribes in darts for hunting.1 The chemical structure was established in 1992 using NMR spectroscopy (proton NMR).2 Epibatidine possesses significant medicinal properties, it functions as an analgesic agent by binding to the nicotinic acetylcholine receptors (nAChRs) instead of the opioid receptors.3 Moreover it displays an affinity for said receptors that is 100- to 200-fold higher than nicotine. The alkaloid interacts with Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels and are expressed central and peripherally. -
INSTITUTO DE QUÍMICA – CAMPUS ARARAQUARA Victor De Sousa Batist
UNIVERSIDADE ESTADUAL PAULISTA “JÚLIO DE MESQUITA FILHO” INSTITUTO DE QUÍMICA – CAMPUS ARARAQUARA Victor de Sousa Batista Estudos de modelagem molecular de compostos bioativos frente ao receptor nicotínico de acetilcolina do subtipo α4β2 Araraquara 2016 Victor de Sousa Batista Estudos de modelagem molecular de compostos bioativos frente ao receptor nicotínico de acetilcolina do subtipo α4β2 Trabalho de Conclusão de Curso apresentado ao Instituto de Química da Universidade Estadual Paulista “Júlio de Mesquita Filho” como parte dos requisitos para a obtenção do título de Bacharel em Química. Orientador: Prof. Dr. Nailton Monteiro do Nascimento Júnior Araraquara 2016 Victor de Sousa Batista Estudos de modelagem molecular de compostos bioativos frente ao receptor nicotínico de acetilcolina do subtipo α4β2 Trabalho de Conclusão de Curso apresentado ao Instituto de Química da Universidade Estadual Paulista “Júlio de Mesquita Filho” como parte dos requisitos para a obtenção do título de Bacharel em Química. Aprovado em _____ de ________________________ de 2016. BANCA EXAMINADORA __________________________________________ Prof. Dr. Nailton Monteiro do Nascimento Júnior Unesp – Araraquara __________________________________________ Prof. Dr. Gustavo Troiano Feliciano Unesp – Araraquara __________________________________________ Profa. Dra. Cíntia Duarte de Freitas Milagre Unesp – Araraquara Araraquara 2016 AGRADECIMENTOS Ao meu orientador, Prof. Dr. Nailton Monteiro do Nascimento Júnior, por sempre me incentivar a ultrapassar meus limites e pela -
Lllostridium Botulinum Neurotoxinl I H
MICROBIOLOGICAL REVIEWS, Sept. 1980, p. 419-448 Vol. 44, No. 3 0146-0749/80/03-0419/30$0!)V/0 Lllostridium botulinum Neurotoxinl I H. WJGIYAMA Food Research Institute and Department ofBacteriology, University of Wisconsin, Madison, Wisconsin 53706 INTRODUCTION ........ .. 419 PATHOGENIC FORMS OF BOTULISM ........................................ 420 Food Poisoning ............................................ 420 Wound Botulism ............................................ 420 Infant Botulism ............................................ 420 CULTURES AND TOXIN TYPES ............................................ 422 Culture-Toxin Relationships ............................................ 422 Culture Groups ............................................ 422 GENETICS OF TOXIN PRODUCTION ......................................... 423 ASSAY OF TOXIN ............................................ 423 In Vivo Quantitation ............................................ 424 Infant-Potent Toxin ............................................ 424 Serological Assays ............................................ 424 TOXIC COMPLEXES ............................................ 425 Complexes 425 Structure of Complexes ...................................................... 425 Antigenicity and Reconstitution .......................... 426 Significance of Complexes .......................... 426 Nomenclature ........................ 427 NEUROTOXIN ..... 427 Molecular Weight ................... 427 Specific Toxicity ................... 428 Small Toxin .................. -
JPET #226803 Title Page Effects of Nicotinic Acetylcholine Receptor
JPET Fast Forward. Published on September 10, 2015 as DOI: 10.1124/jpet.115.226803 This article has not been copyedited and formatted. The final version may differ from this version. 1 JPET #226803 Title Page Effects of nicotinic acetylcholine receptor agonists in assays of acute pain-stimulated and pain- depressed behaviors in rats Kelen. C. Freitas, F. Ivy Carroll, and S. Stevens Negus Downloaded from Department of Pharmacology and Toxicology, Virginia Commonwealth University, jpet.aspetjournals.org Richmond VA, USA Research Triangle Institute, Research Triangle Park, NC, USA at ASPET Journals on September 26, 2021 JPET Fast Forward. Published on September 10, 2015 as DOI: 10.1124/jpet.115.226803 This article has not been copyedited and formatted. The final version may differ from this version. 2 JPET #226803 Running Title Page Effects of nicotinic drugs on pain-depressed behavior Address correspondence to: Kelen Freitas, Department of Pharmacology and Toxicology, Downloaded from Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA 23298. Telephone: (804) 828-3158 Fax: (804) 828-2117 Email: [email protected] jpet.aspetjournals.org Number of text pages: 37 at ASPET Journals on September 26, 2021 Number of tables: 1 Number of figures: 6 Number of references: 76 Number of words in the abstract: 241 Number of words in the introduction: 746 Number of words in the discussion: 1.250 List of non-standard abbreviations nAChRs, nicotinic acetylcholine receptors DhβE, dihydro-ß-ertyroidine MD-354, Meta-chlorophenylguanidine Nicotine, (-)-nicotine hydrogen tartrate PNU 282987, N-(3R)-1-Azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide 5-I-A-85380, 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ICSS, intracranial self-stimulation MCR, maximum control rate %MCR, percentage of MCR ANOVA, analysis of variance JPET Fast Forward. -
Neuronal Nicotinic Receptors
NEURONAL NICOTINIC RECEPTORS Dr Christopher G V Sharples and preparations lend themselves to physiological and pharmacological investigations, and there followed a Professor Susan Wonnacott period of intense study of the properties of nAChR- mediating transmission at these sites. nAChRs at the Department of Biology and Biochemistry, muscle endplate and in sympathetic ganglia could be University of Bath, Bath BA2 7AY, UK distinguished by their respective preferences for C10 and C6 polymethylene bistrimethylammonium Susan Wonnacott is Professor of compounds, notably decamethonium and Neuroscience and Christopher Sharples is a hexamethonium,5 providing the first hint of diversity post-doctoral research officer within the among nAChRs. Department of Biology and Biochemistry at Biochemical approaches to elucidate the structure the University of Bath. Their research and function of the nAChR protein in the 1970’s were focuses on understanding the molecular and facilitated by the abundance of nicotinic synapses cellular events underlying the effects of akin to the muscle endplate, in electric organs of the acute and chronic nicotinic receptor electric ray,Torpedo , and eel, Electrophorus . High stimulation. This is with the goal of affinity snakea -toxins, principallyaa -bungarotoxin ( - Bgt), enabled the nAChR protein to be purified, and elucidating the structure, function and subsequently resolved into 4 different subunits regulation of neuronal nicotinic receptors. designateda ,bg , and d .6 An additional subunit, e , was subsequently identified in adult muscle. In the early 1980’s, these subunits were cloned and sequenced, The nicotinic acetylcholine receptor (nAChR) arguably and the era of the molecular analysis of the nAChR has the longest history of experimental study of any commenced. -
Ion Channels
UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. -
Bioorganic & Medicinal Chemistry Letters
Bioorganic & Medicinal Chemistry Letters 18 (2008) 4651–4654 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl Epiboxidine and novel-related analogues: A convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes Luca Rizzi a, Clelia Dallanoce a,*, Carlo Matera a, Pietro Magrone a, Luca Pucci b, Cecilia Gotti b, Francesco Clementi b, Marco De Amici a a Istituto di Chimica Farmaceutica e Tossicologica ‘‘Pietro Pratesi”, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy b CNR, Istituto di Neuroscienze, Farmacologia Cellulare e Molecolare e Dipartimento Farmacologia, Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, Italy article info abstract Article history: Racemic exo-epiboxidine 3, endo-epiboxidine 6, and the two unsaturated epiboxidine-related derivatives Received 18 June 2008 7 and 8 were efficiently prepared taking advantage of a palladium-catalyzed Stille coupling as the key Revised 3 July 2008 step in the reaction sequence. The target compounds were assayed for their binding affinity at neuronal Accepted 4 July 2008 a4b2 and a7 nicotinic acetylcholine receptors. Epiboxidine 3 behaved as a high affinity a4b2 ligand Available online 10 July 2008 (Ki = 0.4 nM) and, interestingly, evidenced a relevant affinity also for the a7 subtype (Ki = 6 nM). Deriva- tive 7, the closest analogue of 3 in this group, bound with lower affinity at both receptor subtypes Keywords: (K = 50 nM for a4b2 and K = 1.6 lM for a7) evidenced a gain in the a4b2 versus a7 selectivity when Neuronal nicotinic acetylcholine receptors i i compared with the model compound. -
Nicotinic Acetylcholine Receptors
nAChR Nicotinic acetylcholine receptors nAChRs (nicotinic acetylcholine receptors) are neuron receptor proteins that signal for muscular contraction upon a chemical stimulus. They are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the presynaptic and postsynaptic sides of theneuromuscular junction. Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors. Like the other type of acetylcholine receptor-the muscarinic acetylcholine receptor (mAChR)-the nAChR is triggered by the binding of the neurotransmitter acetylcholine (ACh). Just as muscarinic receptors are named such because they are also activated by muscarine, nicotinic receptors can be opened not only by acetylcholine but also by nicotine —hence the name "nicotinic". www.MedChemExpress.com 1 nAChR Inhibitors & Modulators (+)-Sparteine (-)-(S)-B-973B Cat. No.: HY-W008350 Cat. No.: HY-114269 Bioactivity: (+)-Sparteine is a natural alkaloid acting as a ganglionic Bioactivity: (-)-(S)-B-973B is a potent allosteric agonist and positive blocking agent. (+)-Sparteine competitively blocks nicotinic allosteric modulator of α7 nAChR, with antinociceptive ACh receptor in the neurons. activity [1]. Purity: 98.0% Purity: 99.93% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in Water, Size: 10mM x 1mL in DMSO, 100 mg 5 mg, 10 mg, 50 mg, 100 mg (±)-Epibatidine A-867744 (CMI 545) Cat. No.: HY-101078 Cat. No.: HY-12149 Bioactivity: (±)-Epibatidine is a nicotinic agonist. (±)-Epibatidine is a Bioactivity: A-867744 is a positive allosteric modulator of α7 nAChRs (IC50 neuronal nAChR agonist. values are 0.98 and 1.12 μM for human and rat α7 receptor ACh-evoked currents respectively, in X. -
Synthesis of Epiboxidine 36
C H A P T E R - I I Synthesis of Epiboxidine 36 1. Introduction The construction of 7-azabicyclo[2.2.1]heptane framework has seen strong revival immediately after the structural elucidation of epibatidine (1) {exo-2-(6-chloro-3-pyridyl)-7- azabicyclo[2.2.1]heptane}.' Epibatidine (1); the only prominent m e m b e r of this class, as introduced in the previous chapter, has been shown to be a highly potent non-opioid analgesic agent^'® an d a novel nicotinic acetylcholine receptors (nAChRs)^'® agonist. Fig. 1 Although these outstanding pharmacological activities of 1 have kindled interest to recognize this molecule as an useful therapeutically important drug, its high toxicity, * causing death in mice (six out of six) w h e n injected at 10 (iL/ K g scale, has b e c o m e a major impediment in developing this molecule as a drug.® Therefore, there has been continuing research interest towards an alternate p h a r m a c o p h o r e related to the structure 1 capable of exhibiting comparable pharmacological properties but with an enhanced ratio of pharmacological to toxicological activity. In this context, chemists and phamacologists have begun synthesizing compounds analogous to 1 by • altering, extending or cleaving the 7-azabicyclo[2.2.1]heptane framework of 1, keeping the pyridyl ring intact, • adding extra functionalities in the original framework of 1 along with the features described above or, • by combining structural features of the k n o w n alkaloids having high affinity towards nicotinic receptors an d 1.