DOCSLIB.ORG

Bioorganic & Medicinal Chemistry Letters

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
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. Epiboxidine Nicotinic ligands Ó 2008 Elsevier Ltd. All rights reserved. Binding affinity Neuronal nicotinic acetylcholine receptors (nAChRs) make up a (À)-epibatidine 2 (Fig. 1), a highly toxic alkaloid identified in the family of pentameric ligand-gated ion channels, which are formed skin of the Ecuadorian frog Epipedobates tricolor,10 has inspired a by combinations of alpha and beta subunits1,2 or exist as homo- huge amount of research aimed at designing subtype selective nic- pentamers, in the cases of a7, a8, and a9 receptors, which are otinic agonists.1,2,9,11,12 Although the pharmacological effects of inhibited by a-bungarotoxin.3 To date, nine a (a2–a10) and three (À)-2 are mediated by a variety of nAChRs,13 which preclude any b (b2–b4) isoforms have been characterized, though only a rela- therapeutic potential for epibatidine, the analgesic potency, tively small subset of combinations generates functionally and roughly 100 times higher than that of morphine and 30 times high- physiologically relevant channels.4 Nicotinic receptors are widely er than that of nicotine, has been attributed to its high affinity for distributed in the brain, where they primarily modulate the release the a4b2 subtype. Worth mentioning, (À)-2 and (+)-2 are charac- of other neurotransmitters and, to a lesser extent, mediate synaptic terized by similar affinities for nAChRs and almost identical ED50 transmission.5 Neuronal nAChRs, selectively activated by (S)-nico- values in the mouse tail-flick antinociception assay.13d,14,15 tine 1 (Fig. 1), are involved in various processes such as cognition, Among the synthetic epibatidine-related compounds, (±)-epib- learning and memory, cerebral blood flow and metabolism, as well oxidine 3 (Fig. 1), in which the 3-methylisoxazolyl moiety has re- as an array of pathological conditions such as Alzheimer’s and Par- placed the chloropyridinyl ring of the parent derivative, behaved kinson’s diseases, mild cognitive impairment (MCI), schizophrenia, as a potent a4b2 nicotinic receptor agonist, 10-fold less potent than epilepsy, Tourette’s syndrome, anxiety, depression, attention-defi- epibatidine as antinociceptive agent but about 20-fold less toxic.16 cit hyperactivity disorder (ADHD), and nicotine addiction.1,2,6,7 The presence of the 3-methylisoxazole ring was similarly effective The heteromeric a4b2 receptors, the most abundant subtype in in the structure of (S)-ABT-418 4 (Fig. 1), a nicotine-related a4b2 the mammalian CNS, and the homomeric a7 channels are privi- selective full agonist, which entered Phase I for the treatment of leged biological targets in the search for selective nAChR ligands cognitive dysfunction and was later on discontinued.2,7,17 A further with therapeutic potential.2,8 As far as the number of nicotinic ago- relevant example of structural analogue of epibatidine is the unsat- nists isolated from natural sources is taken into consideration,9 urated derivative (±)-UB-165 5, containing the 9-azabicy- clo[4.2.1]nonene skeleton, a high affinity nicotinic partial agonist * Corresponding author. Tel.: +39 02 50319327; fax: +39 02 50319326. which allowed to clarify the involvement of the a4b2 subtype in 18,19 E-mail address: [email protected] (C. Dallanoce). modulating dopamine release from rat striatal synaptosomes. 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.07.016 4652 L. Rizzi et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4651–4654 H Cl H CH3 CH3 N N N N N N O O N N CH3 CH3 1 (S)-Nicotine 2 (−)-Epibatidine 3 (±)-Epiboxidine 4 (S)-ABT-418 H H Cl R CH3 N N N N N O O N CH3 5 (±)-UB-165 6 (±)-endo-Epiboxidine (±)-7: R=H (±)-8: R=CH3 Figure 1. Structures of model and target compounds in this study. In the present study, we aimed at further investigating epibox- Boc idine, that is, at a7 nAChRs, a subtype on which, to the best of our Br N knowledge, it was never assayed. To this end, we thought about a a Br flexible synthesis of (±)-3 allowing also the preparation of unsatu- + N rated structurally related derivatives. Accordingly, we describe a novel synthetic route to epiboxidine 3 (exo-isomer), its epimer Boc CO2Me CO2Me endo-epiboxidine 6, and the two unprecedented dehydro-ana- logues of epiboxidine 7 and 8. The target chiral compounds, whose 13 14 15 structures are reported in Figure 1, were prepared and tested as racemates. Boc As illustrated in the upper part of Scheme 1, the known prepa- N rations of 3 took advantage of the reaction of 7-azabicy- b-d O e,f 15 11 clo[2.2.1]heptane-2,7-dicarboxylic acid diesters 9a and 9b with the dianion of acetone oxime, followed by acidic treatment of intermediates 10a and 10b.16,20 As an alternative approach, we 16 planned to make use of a Stille palladium-catalyzed cross-coupling 21 reaction, which involved the coupling of enoltriflate 11 with 3- H methyl-5-tributylstannylisoxazole 12, as depicted in the lower Cl CH 3 g part of Scheme 1. + 12 N Initially, we made use of a known procedure to prepare 7-tert- HO butoxycarbonyl-7-azabicyclo[2.2.1]heptan-2-one 16, a key inter- SnBu3 22 mediate in one of the syntheses of (±)-epibatidine. The first step 17 18 of the sequence, a [4+2] cycloaddition of N-Boc-pyrrole 13, used in large excess, to methyl 3-bromopropiolate 14, was performed un- Scheme 2. (a) MW, 90 °C, 1.5 h, neat; (b)–(d) see Ref. 22; (e) (iPr)2NH/n-BuLi, der microwave heating (Scheme 2).23 These experimental condi- À78 °C; (f) N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide), À78 °C to rt; (g) NEt /THF, rt, 5 h. tions allowed reduction of the reaction time (from 30 to 1.5 h) 3 and improvement of the yield of the Diels-Alder adduct 15 (from 60% to 85%). Subsequently, we prepared the known trifluorometh- anesulfonate 1124 in 62% isolated yield by treatment of ketone 16 with LDA in THF at À78 °C25 followed by reaction with N-(5- chloro-2-pyridyl)bis(trifluoromethanesulfonimide)26 (Scheme 2). 3-Methyl-5-tributylstannylisoxazole 12 was obtained through the RO2C RO2C OH previously described 1,3-dipolar cycloaddition of tributylethynyl- O N N N 27 a b tin 17 to acetonitrile oxide. As a modification of the known pro- CO2Et 3 CH3 cedure, we chose to isolate the stable precursor of the 1,3-dipole, that is, the acetohydroximoyl chloride 18, which in turn was syn- 9a: R = Et 10a: R = Et thesized by reacting acetaldoxime with benzyltrimethylammoni- 9b: R = tert-Bu 10b: R = tert-Bu 28,29 um tetrachloroiodate (BTMA ICl4). In this way, the target (a) Acetone oxime, nBuLi; (b) conc. HCl, 80ºC. tributylstannylisoxazole 12 was prepared in acceptable yields (45–50%). Boc The Stille cross-coupling reaction of triflate 11 to isoxazole 12, CH3 N performed in the presence of the Tris(dibenzylideneacetone)dipal- OTf ladium(0)-chloroform adduct, triphenylphosphine, and anhydrous 3 + N Bu Sn 3 O ZnCl2, produced the 7-azabicyclo[2.2.1]hept-2-ene derivative 19 in 90% yield (Scheme 3).30 Removal of the N-Boc protection of 19 with 11 12 a 4 N solution of HCl in dioxane afforded the secondary amine 7, Scheme 1. (A) Key steps of the known synthetic strategy to epiboxidine 3. (B) which was converted into the corresponding N-methyl derivative Retrosynthesis of 3 based on a Stille coupling reaction. 8 by a standard reaction with formaldehyde followed by reduction L. Rizzi et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4651–4654 4653 Boc CH3 N a N b,c d 11 O 78 19 Boc Boc CH3 N N e f N b 19 O 3 x HCl O N CH3 20 21 g g b 7 7 fumarate 8 8 fumarate 20 6 x HCl Scheme 3. (a) [Pd2(dba)3]ÁCHCl3, PPh3, 12, anhydrous ZnCl2/THF, À78 °C to rt; (b) 4 N HCl/dioxane, rt; (c) aq Na2CO3; (d) HCHO (37%, aq), NaBH3CN/CH3CN; (e) H2, 10% Pd/C, CH3OH; (f) tert-BuOK/tert-BuOH, reflux, 16 h, flash chromatography; (g) C4H4O4,CH3OH.
Load more

Recommended publications
  • 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.
    [Show full text]
  • (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.
    [Show full text]
  • 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.
    [Show full text]
  • 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
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • NIDA Drug Supply Program Catalog, 25Th Edition
    RESEARCH RESOURCES DRUG SUPPLY PROGRAM CATALOG 25TH EDITION MAY 2016 CHEMISTRY AND PHARMACEUTICS BRANCH DIVISION OF THERAPEUTICS AND MEDICAL CONSEQUENCES NATIONAL INSTITUTE ON DRUG ABUSE NATIONAL INSTITUTES OF HEALTH DEPARTMENT OF HEALTH AND HUMAN SERVICES 6001 EXECUTIVE BOULEVARD ROCKVILLE, MARYLAND 20852 160524 On the cover: CPK rendering of nalfurafine. TABLE OF CONTENTS A. Introduction ................................................................................................1 B. NIDA Drug Supply Program (DSP) Ordering Guidelines ..........................3 C. Drug Request Checklist .............................................................................8 D. Sample DEA Order Form 222 ....................................................................9 E. Supply & Analysis of Standard Solutions of Δ9-THC ..............................10 F. Alternate Sources for Peptides ...............................................................11 G. Instructions for Analytical Services .........................................................12 H. X-Ray Diffraction Analysis of Compounds .............................................13 I. Nicotine Research Cigarettes Drug Supply Program .............................16 J. Ordering Guidelines for Nicotine Research Cigarettes (NRCs)..............18 K. Ordering Guidelines for Marijuana and Marijuana Cigarettes ................21 L. Important Addresses, Telephone & Fax Numbers ..................................24 M. Available Drugs, Compounds, and Dosage Forms ..............................25
    [Show full text]
  • Phenotypic Characterization of an Α4 Neuronal Nicotinic Acetylcholine Receptor Subunit Knock-Out Mouse
    The Journal of Neuroscience, September 1, 2000, 20(17):6431–6441 ␣ Phenotypic Characterization of an 4 Neuronal Nicotinic Acetylcholine Receptor Subunit Knock-Out Mouse Shelley A. Ross,1 John Y. F. Wong,1 Jeremiah J. Clifford,3 Anthony Kinsella,4 Jim S. Massalas,1 Malcolm K. Horne,1 Ingrid E. Scheffer,1,5 Ismail Kola,2 John L. Waddington,3 Samuel F. Berkovic,5 and John Drago1 1Neurosciences Group, Monash University Department of Medicine and 2Institute of Reproduction and Development, Monash Medical Centre, Clayton, Victoria, 3168, Australia, 3Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin 2, Ireland, 4Department of Mathematics, Dublin Institute of Technology, Dublin 8, Ireland, and 5Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, 3084, Australia Neuronal nicotinic acetylcholine receptors (nAChR) are present in tions; conversely, heightened levels of behavioral topographies in high abundance in the nervous system (Decker et al., 1995). Mt were reduced by nicotine in the late phase of the unhabitu- There are a large number of subunits expressed in the brain that ated condition. Ligand autoradiography confirmed the lack of combine to form multimeric functional receptors. We have gen- high-affinity binding to radiolabeled nicotine, cytisine, and epiba- ␣ erated an 4 nAChR subunit knock-out line and focus on defining tidine in the thalamus, cortex, and caudate putamen, although the behavioral role of this receptor subunit. Homozygous mutant binding to a number of discrete nuclei remained. The study ␣ mice (Mt) are normal in size, fertility, and home-cage behavior. confirms the pivotal role played by the 4 nAChR subunit in the Spontaneous unconditioned motor behavior revealed an etho- modulation of a number of constituents of the normal mouse gram characterized by significant increases in several topogra- ethogram and in anxiety as assessed using the plus-maze.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,597,284 B2 Ackermann, Jr
    USO0959.7284B2 (12) United States Patent (10) Patent No.: US 9,597,284 B2 Ackermann, Jr. et al. (45) Date of Patent: *Mar. 21, 2017 (54) DRY EYE TREATMENTS (58) Field of Classification Search USPC .......................................................... 424/400 (71) Applicant: Oyster Point Pharma, Inc., South San See application file for complete search history. Francisco, CA (US) (56) References Cited (72) Inventors: Douglas Michael Ackermann, Jr., San Francisco, CA (US); James Loudin, U.S. PATENT DOCUMENTS Houston, TX (US); Kenneth J. 6,277,855 B1 8, 2001 Yerxa, Mandell, Arlington, MA (US) 2006, OO84656 A1 4/2006 Ziegler et al. 2011 OO86086 A1 4/2011 Johnson et al. (73) Assignee: Oyster Point Pharma, Inc., San 2011 O274628 A1 11/2011 Borschke Francisco, CA (US) 2012,0289572 A1 1 1/2012 Mazurov et al. (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 EP 1214062 B1 11, 2003 U.S.C. 154(b) by 0 days. WO WO-03005998 A2 1, 2003 WO WO-03045394 A1 6, 2003 This patent is Subject to a terminal dis WO WO-2004039366 A1 5, 2004 claimer. WO WO 2006/100075 * 9/2006 WO WO-2008O57938 A1 5, 2008 (21) Appl. No.: 14/887,248 WO WO-2009111550 A1 9, 2009 WO WO-2010O28011 A1 3, 2010 (22) Filed: Oct. 19, 2015 WO WO-2010O28033 A1 3, 2010 (65) Prior Publication Data OTHER PUBLICATIONS US 2016/0106745 A1 Apr. 21, 2016 Mazzanti (Int. J. Devl Neuroscience 25 (2007) 259-264.* Beule (GMS Current Topics in Otorhinolaryngology—Head and Neck Surgery 2010, vol.
    [Show full text]