An Approach to Drug Classification in Psychopharmacology
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INVESTIGATION of NATURAL PRODUCT SCAFFOLDS for the DEVELOPMENT of OPIOID RECEPTOR LIGANDS by Katherine M
INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS By Katherine M. Prevatt-Smith Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. _________________________________ Chairperson: Dr. Thomas E. Prisinzano _________________________________ Dr. Brian S. J. Blagg _________________________________ Dr. Michael F. Rafferty _________________________________ Dr. Paul R. Hanson _________________________________ Dr. Susan M. Lunte Date Defended: July 18, 2012 The Dissertation Committee for Katherine M. Prevatt-Smith certifies that this is the approved version of the following dissertation: INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS _________________________________ Chairperson: Dr. Thomas E. Prisinzano Date approved: July 18, 2012 ii ABSTRACT Kappa opioid (KOP) receptors have been suggested as an alternative target to the mu opioid (MOP) receptor for the treatment of pain because KOP activation is associated with fewer negative side-effects (respiratory depression, constipation, tolerance, and dependence). The KOP receptor has also been implicated in several abuse-related effects in the central nervous system (CNS). KOP ligands have been investigated as pharmacotherapies for drug abuse; KOP agonists have been shown to modulate dopamine concentrations in the CNS as well as attenuate the self-administration of cocaine in a variety of species, and KOP antagonists have potential in the treatment of relapse. One drawback of current opioid ligand investigation is that many compounds are based on the morphine scaffold and thus have similar properties, both positive and negative, to the parent molecule. Thus there is increasing need to discover new chemical scaffolds with opioid receptor activity. -
Blockade of Muscarinic Acetylcholine Receptors Facilitates Motivated Behaviour and Rescues a Model of Antipsychotic- Induced Amotivation
www.nature.com/npp ARTICLE Blockade of muscarinic acetylcholine receptors facilitates motivated behaviour and rescues a model of antipsychotic- induced amotivation Jonathan M. Hailwood 1, Christopher J. Heath2, Benjamin U. Phillips1, Trevor W. Robbins1, Lisa M. Saksida3,4 and Timothy J. Bussey1,3,4 Disruptions to motivated behaviour are a highly prevalent and severe symptom in a number of neuropsychiatric and neurodegenerative disorders. Current treatment options for these disorders have little or no effect upon motivational impairments. We assessed the contribution of muscarinic acetylcholine receptors to motivated behaviour in mice, as a novel pharmacological target for motivational impairments. Touchscreen progressive ratio (PR) performance was facilitated by the nonselective muscarinic receptor antagonist scopolamine as well as the more subtype-selective antagonists biperiden (M1) and tropicamide (M4). However, scopolamine and tropicamide also produced increases in non-specific activity levels, whereas biperiden did not. A series of control tests suggests the effects of the mAChR antagonists were sensitive to changes in reward value and not driven by changes in satiety, motor fatigue, appetite or perseveration. Subsequently, a sub-effective dose of biperiden was able to facilitate the effects of amphetamine upon PR performance, suggesting an ability to enhance dopaminergic function. Both biperiden and scopolamine were also able to reverse a haloperidol-induced deficit in PR performance, however only biperiden was able to rescue the deficit in effort-related choice (ERC) performance. Taken together, these data suggest that the M1 mAChR may be a novel target for the pharmacological enhancement of effort exertion and consequent rescue of motivational impairments. Conversely, M4 receptors may inadvertently modulate effort exertion through regulation of general locomotor activity levels. -
Appendix A: Potentially Inappropriate Prescriptions (Pips) for Older People (Modified from ‘STOPP/START 2’ O’Mahony Et Al 2014)
Appendix A: Potentially Inappropriate Prescriptions (PIPs) for older people (modified from ‘STOPP/START 2’ O’Mahony et al 2014) Consider holding (or deprescribing - consult with patient): 1. Any drug prescribed without an evidence-based clinical indication 2. Any drug prescribed beyond the recommended duration, where well-defined 3. Any duplicate drug class (optimise monotherapy) Avoid hazardous combinations e.g.: 1. The Triple Whammy: NSAID + ACE/ARB + diuretic in all ≥ 65 year olds (NHS Scotland 2015) 2. Sick Day Rules drugs: Metformin or ACEi/ARB or a diuretic or NSAID in ≥ 65 year olds presenting with dehydration and/or acute kidney injury (AKI) (NHS Scotland 2015) 3. Anticholinergic Burden (ACB): Any additional medicine with anticholinergic properties when already on an Anticholinergic/antimuscarinic (listed overleaf) in > 65 year olds (risk of falls, increased anticholinergic toxicity: confusion, agitation, acute glaucoma, urinary retention, constipation). The following are known to contribute to the ACB: Amantadine Antidepressants, tricyclic: Amitriptyline, Clomipramine, Dosulepin, Doxepin, Imipramine, Nortriptyline, Trimipramine and SSRIs: Fluoxetine, Paroxetine Antihistamines, first generation (sedating): Clemastine, Chlorphenamine, Cyproheptadine, Diphenhydramine/-hydrinate, Hydroxyzine, Promethazine; also Cetirizine, Loratidine Antipsychotics: especially Clozapine, Fluphenazine, Haloperidol, Olanzepine, and phenothiazines e.g. Prochlorperazine, Trifluoperazine Baclofen Carbamazepine Disopyramide Loperamide Oxcarbazepine Pethidine -
The Influence of a Muscarinic M1 Receptor Antagonist on Brain Choline Levels in Patients with a Psychotic Disorder and Healthy Controls
MHENS School for Mental Health and Neuroscience The influence of a muscarinic M1 receptor antagonist on brain choline levels in patients with a psychotic disorder and healthy controls. W.A.M. VingerhoetsA,B, G. BakkerA,B, O. BloemenA,C, M. CaanD, J. BooijB, T.A.M.J. van AmelsvoortA. A Department of Psychiatry & Psychology, Maastricht University, Maastricht, The Netherlands.. B Department of Nuclear Medicine, Academic Medical Center, Amsterdam, The Netherlands. C GGZ Centraal, Center for Mental Health Care, Hilversum, The Netherlands D Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands Background • The majority of the patients with a psychotic disorder report cognitive impairments in addition to positive and negative symptoms. • It is well known that the neurotransmitter acetylcholine plays an important role in cognition. • A post-mortem study of chronic schizophrenia patients demonstrated a reduction of up to 75% in the number of the acetylcholine muscarinic M1 receptors (1). • Research has shown that muscarinic cholinergic receptors play a major role in cognitive processes. Objective • To investigate in-vivo whether there are differences in baseline choline levels in the anterior cingulate cortex (ACC) and striatum between recent onset medication-free patients with a psychotic disorder and healthy control subjects. • To investigate in-vivo the influence of a muscarinic antagonist on choline levels in the ACC and striatum in recent onset medication-free patients with Figure 2. Example of a striatal spectrum. a psychotic disorder and healthy control subjects. Results Methods • No significant differences were found in baseline choline levels between the two groups in both the striatum (p=0.336) and the ACC (p=0.479). -
A Comparison of Scopolamine and Biperiden As a Rodent Model for Cholinergic Cognitive Impairment
Psychopharmacology (2011) 215:549–566 DOI 10.1007/s00213-011-2171-1 ORIGINAL INVESTIGATION A comparison of scopolamine and biperiden as a rodent model for cholinergic cognitive impairment Inge Klinkenberg & Arjan Blokland Received: 30 June 2010 /Accepted: 9 January 2011 /Published online: 19 February 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract Keywords Sensorimotor . Motivation . Attention . Rationale The nonselective muscarinic antagonist scopol- Memory. Animal model . Fixed ratio . Progressive ratio . amine hydrobromide (SCOP) is employed as the gold Delayed nonmatching to position . Muscarinic . standard for inducing memory impairments in healthy Acetylcholine humans and animals. However, its use remains controversial due to the wide spectrum of behavioral effects of this drug. Objective The present study investigated whether biperiden Introduction (BIP), a muscarinic m1 receptor antagonist, is to be preferred over SCOP as a pharmacological model for The muscarinic antagonist scopolamine hydrobromide cholinergic memory deficits in rats. This was done by (SCOP) is used as the gold standard for inducing deficits comparing the effects of SCOP and BIP using a battery of in human and animal models of memory dysfunction. operant tasks: fixed ratio (FR5) and progressive ratio Justification for this purpose has been provided by the (PR10) schedules of reinforcement, an attention paradigm cholinergic hypothesis of geriatric memory dysfunction and delayed nonmatching to position task. proposed in the early 1980s by Bartus et al. (1982). The Results SCOP induced diffuse behavioral disruption, which SCOP model is still used extensively for preclinical testing included sensorimotor responding (FR5, 0.3 and 1 mg/kg), of new substances designed to treat cognitive impairment food motivation (PR10, 1 mg/kg), attention (0.3 mg/kg, (e.g., Barak and Weiner 2009; Buccafusco et al. -
Pharmacology and Toxicology of Amphetamine and Related Designer Drugs
Pharmacology and Toxicology of Amphetamine and Related Designer Drugs U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol Drug Abuse and Mental Health Administration Pharmacology and Toxicology of Amphetamine and Related Designer Drugs Editors: Khursheed Asghar, Ph.D. Division of Preclinical Research National Institute on Drug Abuse Errol De Souza, Ph.D. Addiction Research Center National Institute on Drug Abuse NIDA Research Monograph 94 1989 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, DC 20402 Pharmacology and Toxicology of Amphetamine and Related Designer Drugs ACKNOWLEDGMENT This monograph is based upon papers and discussion from a technical review on pharmacology and toxicology of amphetamine and related designer drugs that took place on August 2 through 4, 1988, in Bethesda, MD. The review meeting was sponsored by the Biomedical Branch, Division of Preclinical Research, and the Addiction Research Center, National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder’s permission is required. All other matieral in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. -
In Vivo Olanzapine Occupancy of Muscarinic Acetylcholine Receptors in Patients with Schizophrenia Thomas J
In Vivo Olanzapine Occupancy of Muscarinic Acetylcholine Receptors in Patients with Schizophrenia Thomas J. Raedler, M.D., Michael B. Knable, D.O., Douglas W. Jones, Ph.D., Todd Lafargue, M.D., Richard A. Urbina, B.A., Michael F. Egan, M.D., David Pickar, M.D. , and Daniel R. Weinberger, M.D. Olanzapine is an atypical antipsychotic with potent than low-dose in the same regions. Muscarinic occupancy ϭ antimuscarinic properties in vitro (Ki 2–25 nM). We by olanzapine ranged from 13% to 57% at 5 mg/dy and studied in vivo muscarinic receptor occupancy by 26% to 79% at 20 mg/dy with an anatomical pattern olanzapine at both low dose (5 mg/dy) and high dose (20 indicating M2 subtype selectivity. The [I-123]IQNB data mg/dy) in several regions of cortex, striatum, thalamus and indicate that olanzapine is a potent and subtype-selective pons by analyzing [I-123]IQNB SPECT images of seven muscarinic antagonist in vivo, perhaps explaining its low schizophrenia patients. Both low-dose and high-dose extrapyramidal side effect profile and low incidence of olanzapine studies revealed significantly lower anticholinergic side effects. [Neuropsychopharmacology [I-123]IQNB binding than that of drug-free schizophrenia 23:56–68, 2000] Published by Elsevier Science Inc. on patients (N ϭ 12) in all regions except striatum. behalf of the American College of Neuropsychopharmacology [I-123]IQNB binding was significantly lower at high-dose KEY WORDS: Muscarinic receptor; Olanzapine; IQNB; cologically (Watling et al. 1995) and correspond to SPECT; Schizophrenia; Antipsychotic genes (respectively, m1–m5) that have been cloned (Bonner et al. -
Mnemonic and Behavioral Effects of Biperiden, an M1-Selective Antagonist, in the Rat
Psychopharmacology https://doi.org/10.1007/s00213-018-4899-3 ORIGINAL INVESTIGATION Mnemonic and behavioral effects of biperiden, an M1-selective antagonist, in the rat Anna Popelíková1 & Štěpán Bahník2 & Veronika Lobellová1 & Jan Svoboda1 & Aleš Stuchlík1 Received: 6 October 2017 /Accepted: 9 April 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Rationale There is a persistent pressing need for valid animal models of cognitive and mnemonic disruptions (such as seen in Alzheimer’s disease and other dementias) usable for preclinical research. Objectives We have set out to test the validity of administration of biperiden, an M1-acetylcholine receptor antagonist with central selectivity, as a potential tool for generating a fast screening model of cognitive impairment, in outbred Wistar rats. Methods We used several variants of the Morris water maze task: (1) reversal learning, to assess cognitive flexibility, with probe trials testing memory retention; (2) delayed matching to position (DMP), to evaluate working memory; and (3) Bcounter-balanced acquisition,^ to test for possible anomalies in acquisition learning. We also included a visible platform paradigm to reveal possible sensorimotor and motivational deficits. Results A significant effect of biperiden on memory acquisition and retention was found in the counter-balanced acquisition and probe trials of the counter-balanced acquisition and reversal tasks. Strikingly, a less pronounced deficit was observed in the DMP. No effects were revealed in the reversal learning task. Conclusions Based on our results, we do not recommend biperiden as a reliable tool for modeling cognitive impairment. Keywords Anticholinergics . Muscarinic receptors . Learning . Memory . Morris water maze . Rat Abbreviations DMSO Dimethyl-sulfoxide Ach Acetylcholine GABA Gamma-amino-butyric acid AChR Acetylcholine receptors GPCRs G-Protein coupled receptors AD Alzheimer’sdisease i.p. -
Wo 2010/075090 A2
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 1 July 2010 (01.07.2010) WO 2010/075090 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 409/14 (2006.01) A61K 31/7028 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 409/12 (2006.01) A61P 11/06 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2009/068073 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 15 December 2009 (15.12.2009) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, (26) Publication Language: English TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/122,478 15 December 2008 (15.12.2008) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): AUS- ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, PEX PHARMACEUTICALS, INC. -
Prohibited Substances List
Prohibited Substances List This is the Equine Prohibited Substances List that was voted in at the FEI General Assembly in November 2009 alongside the new Equine Anti-Doping and Controlled Medication Regulations(EADCMR). Neither the List nor the EADCM Regulations are in current usage. Both come into effect on 1 January 2010. The current list of FEI prohibited substances remains in effect until 31 December 2009 and can be found at Annex II Vet Regs (11th edition) Changes in this List : Shaded row means that either removed or allowed at certain limits only SUBSTANCE ACTIVITY Banned Substances 1 Acebutolol Beta blocker 2 Acefylline Bronchodilator 3 Acemetacin NSAID 4 Acenocoumarol Anticoagulant 5 Acetanilid Analgesic/anti-pyretic 6 Acetohexamide Pancreatic stimulant 7 Acetominophen (Paracetamol) Analgesic/anti-pyretic 8 Acetophenazine Antipsychotic 9 Acetylmorphine Narcotic 10 Adinazolam Anxiolytic 11 Adiphenine Anti-spasmodic 12 Adrafinil Stimulant 13 Adrenaline Stimulant 14 Adrenochrome Haemostatic 15 Alclofenac NSAID 16 Alcuronium Muscle relaxant 17 Aldosterone Hormone 18 Alfentanil Narcotic 19 Allopurinol Xanthine oxidase inhibitor (anti-hyperuricaemia) 20 Almotriptan 5 HT agonist (anti-migraine) 21 Alphadolone acetate Neurosteriod 22 Alphaprodine Opiod analgesic 23 Alpidem Anxiolytic 24 Alprazolam Anxiolytic 25 Alprenolol Beta blocker 26 Althesin IV anaesthetic 27 Althiazide Diuretic 28 Altrenogest (in males and gelidngs) Oestrus suppression 29 Alverine Antispasmodic 30 Amantadine Dopaminergic 31 Ambenonium Cholinesterase inhibition 32 Ambucetamide Antispasmodic 33 Amethocaine Local anaesthetic 34 Amfepramone Stimulant 35 Amfetaminil Stimulant 36 Amidephrine Vasoconstrictor 37 Amiloride Diuretic 1 Prohibited Substances List This is the Equine Prohibited Substances List that was voted in at the FEI General Assembly in November 2009 alongside the new Equine Anti-Doping and Controlled Medication Regulations(EADCMR). -
(19) United States (12) Patent Application Publication (10) Pub
US 20130210835A1 (19) United States (12) Patent Application Publication (10) Pub. N0.2 US 2013/0210835 A1 Mitchell (43) Pub. Date: Aug. 15, 2013 (54) PHARMACEUTICAL COMPOSITIONS Publication Classi?cation (75) Inventor: Odes W. Mitchell; Arlington, TX (U S) (51) Int. Cl. A61K31/137 (2006.01) _ A611; 31/4402 (2006.01) (73) Ass1gnee: GM PHARMACEUTICAL, INC, A61K 31/485 (200601) Arhngton, TX (Us) A611; 31/09 (2006.01) _ A611; 31/495 (2006.01) (21) App1.No.. 13/703,584 A61K31/505 (200601) 22 PCT P1 d: J .13 2011 (52) us Cl ( ) 1e “n ’ CPC ........... .. A611; 31/137 (2013.01); A611;31/495 (86) PCT NO. PCT/“11,4031 (2013.01); A611;31/505 (2013.01); A611; 31/485 (2013.01); A611; 31/09 (2013.01); § 371 (0)0). A611;31/4402 (2013.01) (2), (4) Date: Feb- 2, 2013 USPC .... .. 514/255.04; 564/355; 514/653; 544/396; 544/332; 514/275; 546/74; 514/289; 514/282; Related US. Application Data 514657; 514652 (60) Provisional application No. 61/354,061; ?led on Jun. (57) ABSTRACT 11; 2010; provisional application No. 61/354,057; A composition of an antitussive; a decongestant; or an anti ?led on Jun. 11; 2010; provisional application No. histamine to treat respiratory and oral pharyngeal congestion 61/354,053; ?led on Jun. 11,2010. and related symptoms in a patient. US 2013/0210835 A1 Aug. 15,2013 PHARMACEUTICAL COMPOSITIONS mucus build-up to clear congestion in the air passages. Symp toms due to allergies or allergens are often treated With an CROSS-REFERENCES TO RELATED antihistamine. -
Proper Use of Ketamine and Innovar
Proper Use of Ketamine and lnnovar* GUENTER CORSSEN, M.D. Professor and Chairman, Department of Anesthesiology, University of Alabama School of Medicine, Birmingham, Alabama KETAMINE. Success or failure with the use of Use of ketamine predominantly in infants ketamine depends largely on three factors: and children up to 14 years of age. 1. Awareness that ketamine is different from traditional anesthetics. These differences in The use of ketamine in adult patients is con clude the following: fined to surgical conditions for which keta mine has proven to be particularly advan Ketamine, unlike traditional anesthetics tageous, safe, and superior to conventional which cause total depression of the central anesthetic agents and methods ( see under 3). nervous system, affects selectively pain con duction and perception systems, stimulating Narcotic addicts and patients with a history one area of the brain while simultaneously of chronic alcohol abuse or suffering from depressing another ("dissociation") . acute alcohol intoxication are poor candi dates for ketamine anesthesia because in Ketamine stimulates the cardiovascular sys these patients even excessive doses of keta tem while traditional anesthetics depress car mine may fail to control body movements. diovascular function. 3. Limiting the use of ketamine anesthesia to Ketamine has antiarrhythmic properties while the following specific surgical areas and con traditional anesthetics do not. They may ditions: even precipitate arrhythmias. Surgical treatment of burns* Ketamine maintains or even exaggerates pro tective reflexes while traditional anesthetics Neurodiagnostic procedures such as pneu suppress them. moencephalography, ventriculography, mye lography, and carotid arteriography. Ketamine ensures airway patency, provided no mechanical airway obstruction is present, Out-patient ophthalmology (tonometry, fun while traditional anesthetics require addi doscopy, gonioscopy).