LSD — My Problem Child Albert Hofmann
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United States Patent (19) [11] 3,968,111 Bach Et Al
United States Patent (19) [11] 3,968,111 Bach et al. (45) July 6, 1976 54 8,8-DISUBSTITUTED-6- 3,113,133 12/1963 Hofmann et al..w. 260/285.5 METHYLERGOLINES AND RELATED COMPOUNDS Primary Examiner-Alton D. Rollins 75) inventors: Nicholas J. Bach; Edmund C. Assistant Examiner-Mary Vaughn Kornfeld, both of Indianapolis, Ind. Attorney, Agent, or Firm-James L. Rowe, Everet F. 73) Assignee: Eli Lilly and Company, Indianapolis, Smith Ind. 22 Filed: Dec. 6, 1974 21 Appl. No.: 530,320 57 ABSTRACT 8,8-Disubstituted-6-methylergolines and 9-ergolenes, 52 U.S. Cl............................... 260/285.5; 424/261 prepared by alkylation of lysergic, isolysergic or their 51 int. C.’................ C07D 457/02; C07D 457/10 9,10-dihydro analogues, optionally followed by chemi 58) Field of Search.................................. 260/285.5 cal modification of an 8-substituent. 56 References Cited UNITED STATES PATENTS 9 Claims, No Drawings 2,86,074 1 1/1958 Kornfeld et al.................. 260/285.5 3,968, 111 1 2 1722 (1957) prepared the 8-methyl derivative of D-iso 8,8-DISUBSTITUTED-6-METHYLERGOLINES AND lysergic acid diethylamide, stating that they were, how RELATED COMPOUNDS ever, unable to obtain substitution at C8 using dihydro lysergic acid methyl ester and the alkylating agent used BACKGROUND OF THE INVENTION successfully with lysergic acid itself; to wit, methylio Compounds based on the ergoline ring system dide and potassium amide. These authors also prepared 8-ethyl-D-isolysergic acid diethylamide and the 1,8- dimethyl-D-isolysergic acid diethylamide. There is no mention in the literature of an 8,8-disubstituted-9-ergo O lene in which the substituents at 8 are other than amide groups and in which the 1-position is not substituted. -
Introduction to the Pharmacology of Ergot Alkaloids and Related Compounds As a Basis of Their Therapeutic Application
CHAPTER I Introduction to the Pharmacology of Ergot Alkaloids and Related Compounds as a Basis of Their Therapeutic Application B. BERDE and E. STURMER "Truth is rarely pure and never simple" OSCAR WILDE This chapter, rather unorthodox for a volume of the Handbook of Experimental Pharmacology, is not intended as a summary of the wealth of information accumu- lated in this book. It is an attempt at a compact synopsis to help those teaching pharmacology or writing a textbook of pharmacology not to overlook the essential chemical and biological basis of the therapeutically most important compounds and those of their activities which are believed to be relevant for their therapeutic effects. The present volume, entitled Ergot Alkaloids and Related Compounds, deals with chemical entities containing the tetracyclic ergolene- or ergoline-ring system. They can be obtained by extraction of different strains of the fungus cIaviceps- grown on rye or cultivated in fermentation tanks-or alternatively by partial or total synthesis. These compounds can be divided into four main structural groups: cIavine alkaloids, lysergic acids, simple lysergic acid-amides, and peptide alkaloids. One example of each type of molecule is given in Figure 1. The degree of oxidation is a criterion for further differentiation in the group of cIavine alkaloids, all of which are compounds of minor biological importance. The naturally occurring lysergic acids are divided into compounds with a double bond in the 8-9 position (8-ergolenes) and in the 9-10 position (9-ergolenes). All congeners are methylated in position (i. The two asymmetric carbon atoms in position 5 and 10 (in the case of 8-ergolenes) or 5 and 8 (in the case of Glavine-Alkaloids Lysergic Acid group Lysergic Acid Amides Peptide-Alkaloids of Alkaloids Examples: I'_ GOOH I"'" NH'GH3 b ~HN Elymoclavine D-Lysergic Acid Ergometrine Ergotamine Fig. -
Modified Monoterpene Indole Alkaloid Production in the Yeast Saccharomyces Cerevisiae Copyright © 2017 by Amy M. Ehrenworth
MODIFIED MONOTERPENE INDOLE ALKALOID PRODUCTION IN THE YEAST SACCHAROMYCES CEREVISIAE A Dissertation Presented to The Academic Faculty by Amy M. Ehrenworth In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the School of Chemistry and Biochemistry Georgia Institute of Technology December, 2017 COPYRIGHT © 2017 BY AMY M. EHRENWORTH MODIFIED MONOTERPENE INDOLE ALKALOID PRODUCTION IN THE YEAST SACCHAROMYCES CEREVISIAE Approved by: Dr. Pamela Peralta-Yahya, Advisor Dr. Francesca Storici School of Chemistry and Biochemistry School of Biological Studies Georgia Institute of Technology Georgia Institute of Technology Dr. M.G. Finn Dr. Loren Williams School of Chemistry and Biochemistry School of Chemistry and Biochemistry Georgia Institute of Technology Georgia Institute of Technology Dr. Wendy L. Kelly School of Chemistry and Biochemistry Georgia Institute of Technology Date Approved: August 14, 2017 ACKNOWLEDGEMENTS I would like to thank all those who’ve guided me on my scientific and personal journey. I was blessed by the circumstances that have led me to this point, and I hope to make those who have influenced and inspired me proud. I want to express gratitude to my advisor Pamela Peralta-Yahya for all she has done for me in my time at Georgia Tech- from introducing me to the incredible field of synthetic biology and sharing her knowledge to helping make me a better scientist. I admire her dedication and ambition, and I am honored to have helped establish the Peralta-Yayha lab. I also appreciate the guidance I’ve received from all of my committee members throughout the years, be it via scientific discussions, mentorship, or personal inspiration. -
Dihydroergotoxine Mesylate
Dihydroergotoxine mesylate sc-203921 Material Safety Data Sheet Hazard Alert Code Key: EXTREME HIGH MODERATE LOW Section 1 - CHEMICAL PRODUCT AND COMPANY IDENTIFICATION PRODUCT NAME Dihydroergotoxine mesylate STATEMENT OF HAZARDOUS NATURE CONSIDERED A HAZARDOUS SUBSTANCE ACCORDING TO OSHA 29 CFR 1910.1200. NFPA FLAMMABILITY1 HEALTH2 HAZARD INSTABILITY0 SUPPLIER Santa Cruz Biotechnology, Inc. 2145 Delaware Avenue Santa Cruz, California 95060 800.457.3801 or 831.457.3800 EMERGENCY: ChemWatch Within the US & Canada: 877-715-9305 Outside the US & Canada: +800 2436 2255 (1-800-CHEMCALL) or call +613 9573 3112 SYNONYMS "C31-H41-N5-O5.C-H4-O3-S: C35-H41-N5-O5.C-H4-O3-S: C32-H43.N5-O5.C-", H4-O3-S, "a mixture in equal proportions of", "dihydroergocornine mesylate, dihydroergocristine mesylate and", "dihydroergocryptine mesylate (alpha-and beta-forms) 1.5:2.5:1", "dihydroergotoxine mesilate", "dihydroergotoxine mesylate", "dihydroergotoxine methanesulphonate", "dihydroerotoxin mesylate", "dihydrogenated ergot alkaloids", "ergoloid mesylate", "hydrogenated ergot alkaloids", "ergotoxine, dihydro-, monomethanesulfonate", CCK-179, Circanol, "CO-Dergocrine mesylate", "Codergocrine Mesylate", Coristin, Dacoren, DCCK, Deapril-ST, DH-Ergotoxin-forte, Dulcion, Ergodilat, Ergoplus, Hydergin, Hydergina, Hydergine, Ischelium, Niloric, Optamine, Perenan, Progeril, Redergam, Segolan, Secatoxin, Redergin, "ergot alkaloid" Section 2 - HAZARDS IDENTIFICATION CHEMWATCH HAZARD RATINGS Min Max Flammability: 1 Toxicity: 2 Body Contact: 2 Min/Nil=0 Low=1 Reactivity: 1 Moderate=2 High=3 Chronic: 3 Extreme=4 CANADIAN WHMIS SYMBOLS 1 of 8 EMERGENCY OVERVIEW RISK Harmful if swallowed. May cause harm to the unborn child. Possible risk of impaired fertility. Irritating to eyes, respiratory system and skin. POTENTIAL HEALTH EFFECTS ACUTE HEALTH EFFECTS SWALLOWED ! Accidental ingestion of the material may be harmful; animal experiments indicate that ingestion of less than 150 gram may be fatal or may produce serious damage to the health of the individual. -
Nomination Background: Hydergine (CASRN: 8067-24-1)
SUMMARY OF DATA FOR CHEMICAL SELECTION Hydergine®1 8067-24-1 BASIS OF NOMINATION TO THE CSWG Hydergine was identified from a review of substances being promoted as nootropics or "smart drugs" for cognition enhancement in well persons of all ages. Hydergine is also a prescription drug for the treatment of senility and cerebrovascular insufficiency. Hydergine is an ergot alkaloid. Ergot alkaloids have a wide field of therapeutic application, and their biological activities are strongly dependent on their structural conformation. Despite their widespread use, little information on the carcinogenic or mutagenic potential of hydergine or closely related ergot alkaloids was found in the available literature. Information on the genotoxicity of hydergine was mixed and not completely consistent with the results reported for the closely related compound, ergotamine. SELECTION STATUS ACTION BY CSWG: 12/16/99 Studies requested: Standard battery of genotoxicity tests including Ames Salmonella and micronucleus assays Priority: The CSWG does not assign priority to genotoxicity testing Rationale/Remarks: An ergot alkaloid prescription drug recently promoted for use as a “smart drug” for healthy individuals seeking cognition enhancement Mixed results regarding genotoxicity; no information on carcinogenicity Ergot alkaloids have a wide range of effects influenced by small changes in structure which affect receptor site binding 1Hydergine® is a registered trademark of Sandoz Pharmaceuticals; the drug will be referred to as "hydergine" for the purpose of -
ESI-Mass Spectrometric and HPLC Elucidation of a New Ergot Alkaloid
Toxicology Mechanisms and Methods Toxicology Mechanisms and Methods, 2011; 21(8): 606–621 2011 © 2011 Informa Healthcare USA, Inc. ISSN 1537-6516 print/ISSN 1537-6524 online 00 DOI: 10.3109/15376516.2011.572934 00 000 RESEARCH ARTICLE 000 28 January 2011 ESI-Mass spectrometric and HPLC elucidation of a new ergot 10 March 2011 alkaloid from perennial ryegrass hay silage associated with bovine reproductive problems 13 March 2011 1537-6516 Andreas F. Lehner1, Jennifer M. Duringer2, Charles T. Estill3, Thomas Tobin4, and A. Morrie Craig5 1537-6524 1Michigan State University, Diagnostic Center for Population & Animal Health, Lansing, Michigan 48910, USA, 2Oregon State University, Department of Environmental & Molecular Toxicology, Corvallis Oregon 97331, USA, 3Oregon State © 2011 Informa Healthcare USA, Inc. University, Department of Clinical Sciences, College of Veterinary Medicine, Corvallis Oregon 97331, USA, 4University of Kentucky, Department of Veterinary Science, Maxwell H. Gluck Equine Research Center, Lexington Kentucky 40546, 10.3109/15376516.2011.572934 USA, and 5Oregon State University, Department of Biomedical Sciences, College of Veterinary Medicine, Corvallis Oregon UTXM 97331, USA 572934 Abstract This case report involves four dairies in the Willamette Valley, Oregon, which experienced reproductive problems associated with the presence of a large, previously unidentified, peak eluting at 5 min in a standard ergovaline high- performance liquid chromatography assay of perennial ryegrass silage fed to those animals. Mycotoxin analysis of the silage was negative, as was serological screening of the herds for infectious bovine rhinotracheitis, bovine diarrhea virus and Leptospirosis, including culturing of urine for Leptospira hardjo hardjobovis. Prolactin concentrations were low in most cattle, consistent with ingestion of ergot alkaloids. -
New Information of Dopaminergic Agents Based on Quantum Chemistry Calculations Guillermo Goode‑Romero1*, Ulrika Winnberg2, Laura Domínguez1, Ilich A
www.nature.com/scientificreports OPEN New information of dopaminergic agents based on quantum chemistry calculations Guillermo Goode‑Romero1*, Ulrika Winnberg2, Laura Domínguez1, Ilich A. Ibarra3, Rubicelia Vargas4, Elisabeth Winnberg5 & Ana Martínez6* Dopamine is an important neurotransmitter that plays a key role in a wide range of both locomotive and cognitive functions in humans. Disturbances on the dopaminergic system cause, among others, psychosis, Parkinson’s disease and Huntington’s disease. Antipsychotics are drugs that interact primarily with the dopamine receptors and are thus important for the control of psychosis and related disorders. These drugs function as agonists or antagonists and are classifed as such in the literature. However, there is still much to learn about the underlying mechanism of action of these drugs. The goal of this investigation is to analyze the intrinsic chemical reactivity, more specifcally, the electron donor–acceptor capacity of 217 molecules used as dopaminergic substances, particularly focusing on drugs used to treat psychosis. We analyzed 86 molecules categorized as agonists and 131 molecules classifed as antagonists, applying Density Functional Theory calculations. Results show that most of the agonists are electron donors, as is dopamine, whereas most of the antagonists are electron acceptors. Therefore, a new characterization based on the electron transfer capacity is proposed in this study. This new classifcation can guide the clinical decision‑making process based on the physiopathological knowledge of the dopaminergic diseases. During the second half of the last century, a movement referred to as the third revolution in psychiatry emerged, directly related to the development of new antipsychotic drugs for the treatment of psychosis. -
Ergot Alkaloids Structure Diversity, Biosynthetic Gene Clusters And
View Online NPR Dynamic Article LinksC< Cite this: Nat. Prod. Rep., 2011, 28, 496 www.rsc.org/npr REVIEW Ergot alkaloids: structure diversity, biosynthetic gene clusters and functional proof of biosynthetic genes Christiane Wallwey and Shu-Ming Li* Received 26th October 2010 DOI: 10.1039/c0np00060d Covering: 2000 to 2010 Ergot alkaloids are toxins and important pharmaceuticals which are produced biotechnologically on an industrial scale. They have been identified in two orders of fungi and three families of higher plants. The most important producers are fungi of the genera Claviceps, Penicillium and Aspergillus (all belonging to the Ascomycota). Chemically, ergot alkaloids are characterised by the presence of a tetracyclic ergoline ring, and can be divided into three classes according to their structural features, i.e. amide- or peptide-like amide derivatives of D-lysergic acid and the clavine alkaloids. Significant progress has been achieved on the molecular biological and biochemical investigations of ergot alkaloid biosynthesis in the last decade. By gene cloning and genome mining, gene clusters for ergot alkaloid biosynthesis have been identified in at least 8 different ascomycete species. Functions of most structure genes have been assigned to reaction steps in the biosynthesis of ergot alkaloids by gene inactivation experiments or biochemical characterisation of the overproduced proteins. Downloaded by NUI Galway on 25 February 2011 1 Introduction 5.2 Identification of gene clusters from genome Published on 24 December 2010 http://pubs.rsc.org -
The Effects of Dihydroergocornine on the Circulation in the Extremities of Man
THE EFFECTS OF DIHYDROERGOCORNINE ON THE CIRCULATION IN THE EXTREMITIES OF MAN Daniel W. Hayes, … , Bayard T. Horton, Gustavus A. Peters J Clin Invest. 1949;28(4):615-620. https://doi.org/10.1172/JCI102111. Research Article Find the latest version: https://jci.me/102111/pdf THE EFFECTS OF DIHYDROERGOCORNINE ON THE CIRCULATION IN THE EXTREMITIES OF MAN By DANIEL W. HAYES,1 KHALIL G. WAKIM, BAYARD T. HORTON, AND GUSTAVUS A. PETERS (From the Divisions of Medicine and Physiology, Mayo Foundation and Mayo Clinic, Rochester, Minnesota) (Received for publication September 28, 1948) Since the advent of therapeutic surgical pro- METHODS cedures on the autonomic nervous system, in- A group of 20 patients with various primary diagnoses, creased interest has been shown in drugs which including Meniere's syndrome, multiple sclerosis, head- block this fairly complex and enigmatic part of the aches of various types and hypertension, volunteered for nervous system. One of these drugs is a derivative this study. The ages varied between 20 and 63 years. of ergot, called Before the observations were begun, the patient re- dihydroergocornine (DHO-180). clined quietly on a comfortable test bed for at least 30 Some of its clinical applications have been re- minutes, in a constant temperature room at 770 F. with ported by several workers, (1-6), showing prin- a humidity of about 40 per cent. The blood flow in all cipally its effects in hypertension, in which a low- four extremities was measured by means of the venous ering of blood pressure was obtained. Bluntschli occlusion plethysniograph with a compensating spirometer and Goetz cases in which recorder (10). -
United States Patent (19) (Ii) 4,246,265 Kornfeld Et Al
United States Patent (19) (ii) 4,246,265 Kornfeld et al. 45) Jan. 20, 1981 (54 6-N-PROPYL-8a-METHOXYMETHYLOR (56) References Cited ANDMETHYLMERCAPTOMETHYLERGOLINEs RELATED COMPOUNDS E U.S. PATENT DOCUMENTS 3,90,894 8/1975 Kornfeld et al. .................... 424/261 75) Inventors: Edmund C. Kornfeld; Nicholas . 4,66, 82 8/1979 Kornfeld et al. .................... 424/26 Bach, both of Indianapolis, Ind. OTHER PUBLICATIONS Stutz et al., J. Med. Chem., 21, 754 (1978). (73) Assignee: Eli Lilly and Company, Indianapolis, - Ind. Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-James L. Rowe; Arthur R. (21) Appl. No.: 80,768 Whale (57) ABSTRACT 22 Filed: Oct. 1, 1979 D-6-n-propyl-8a-methoxymethyl or methylmercap tomethylergoline, dopaminergic drugs are used to treat 51) Int. Cl............................................... A61v 31/48 Parkinsonism and to inhibit prolactin secretion. 52 U.S. C. ................ a 8 a so sa a was 8 o w w a : 58 Field of Search ......................................... 424/26 4 Claims, No Drawings 4,246,265 2 ens and Schaar, Proc. Soc. Exp. Biol. Med., 139, 659-662 6-N-PROPYL-8O-METHOXYMETHYL OR (1972), Bach and Kornfeld, Tetrahedron Letters, 3225 METHYLMERCAPTOMETHYLERGOLINES AND (1974) and Sweeney, Clemens, Kornfeld and Poore, RELATED COMPOUNDS 64th Annual Meeting, American Association for Can cer Research, April 1973. Recently issued patents in the BACKGROUND OF THE INVENTION field of the ergolines or of lysergic acid derivatives Compounds based on the ergoline ring system: include the following: U.S. Pat. No. 3,923,812, U.S. Pat. No. 3,929,796, U.S. Pat. No. 3,944,582, U.S. -
ASPECTS of the PRODUCTION of ALKALOIDS in PENICILLIUM and CLAVICEPS. a Thesis Submitted in Fulfilment of the Requirements Of
ASPECTS OF THE PRODUCTION OF ALKALOIDS IN PENICILLIUM AND CLAVICEPS. A thesis submitted in fulfilment of the requirements of the University of London for the award, Ph.D. JULY 1990 Jane Marina Boyes-Korkis Department of Biochemistry Imperial College of Science, Technology and Medicine, London. SW7. ABSTRACT. [*4C-carbonyl]-anthranilic acid has been used as a biosynthetic probe in a search for novel benzodiazepines. A novel benzodiazepine comprising anthranilic acid and leucine, which together form the benzodiazepine nucleus, and which is substituted by a cyclic glutarimide function has been isolated from liquid cultures of Penicillium aurantiogriseum. In addition a novel diketopiperazine comprising tryptophan and phenylalanine has been isolated. The novel diketopiperazine contains an inverted isoprene group and also exhibits rather rare N-acetylation of the indolic moiety. The structures of the novel compounds were determined by a combination of spectroscopic techniques, particularly JH- and 13C-NMR spectroscopy. Confirmation of the participation of anthranilic acid, leucine and glutamate in the biosynthesis of the benzodiazepine and of the involvement of tryptophan in the formation of the diketopiperazine has been achieved by radiolabelled precursor feeding experiments. Process development of large-scale fermentation of P. aurantiogriseum was necessary to obtain a sufficient amount of each metabolite for structural determination and so the dynamics of the fermentation were also followed. As a prelude to isolation of the enzyme catalysing an isoprenyl- ation step in secondary biosynthesis of P. aurantiogriseum a model system, appertaining to the first enzyme in alkaloid biosynthesis in C laviceps, has been explored for experience, critical appraisal and development of the special techniques involved. -
Proving: LSD (Lysergic Acid) Date: October 1999 by Misha Norland & the School of Homeopathy
Orchard Leigh · Rodborough Hill · Stroud · Gloucestershire · England · GL5 3SS T: +44 (0)1453 765 956 · F: +44 (0)1453 765 953 · E: [email protected] www.alternative-training.com Proving: LSD (Lysergic Acid) Date: October 1999 By Misha Norland & The School of Homeopathy. If the doors of perception were cleansed everything would appear to man as it is, infinite. For man has closed himself up till he sees all things thro' narrow chinks of his cavern. William Blake from The Marriage of Heaven & Hell Lysergic Acid It is a multiple million eyed monster it is hidden in all its elephants and selves it hummeth in the electric typewriter it is electricity connected to itself, if it hath wires it is a vast Spiderweb and I am on the last millionth infinite tentacle of the spiderweb, a worrier lost, separated, a worm, a thought, a self… I Allen Ginsberg a separate consciousness I who want to be God… Allen Ginsberg Introduction School of Homeopathy, February 1999 by Misha Norland LSD 25 is the most potent psychotropic substance known to us, a mere sixth of a milligram being sufficient to induce and maintain an altered state for up to six hours. Furthermore, this initial experience may produce flashback experiences for years to come. It was the main drug informing the youth culture of Western countries in the sixties and seventies. This is well documented in literature, painting and music. The vernacular language of the sixties serves as an example of the infiltration: the trip, a word coined for the LSD experience may be so far out, it is outa sight.