DOCSLIB.ORG

Emerging Targets for Antidepressant Therapies Jeffrey J Rakofsky1, Paul E Holtzheimer2 and Charles B Nemeroff2

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Emerging Targets for Antidepressant Therapies Jeffrey J Rakofsky1, Paul E Holtzheimer2 and Charles B Nemeroff2 Available online at www.sciencedirect.com Emerging targets for antidepressant therapies Jeffrey J Rakofsky1, Paul E Holtzheimer2 and Charles B Nemeroff2 Despite adequate antidepressant monotherapy, the majority of 70% of depressed patients have residual symptoms [3], depressed patients do not achieve remission. Even optimal and and, even with more aggressive therapies, 20% or more aggressive therapy leads to a substantial number of patients may show only a limited response [4]. Rather than being who show minimal and often only transient improvement. In the exception, recurrent episodes are the rule, and there order to address this substantial problem of treatment-resistant are few evidence-based approaches to help clinicians depression, a number of novel targets for antidepressant maintain a patient’s antidepressant response. Persistent therapy have emerged as a consequence of major advances in depression is associated with an increase in substance and the neurobiology of depression. Three major approaches to alcohol abuse, an increased risk for suicide and for car- uncover novel therapeutic interventions are: first, optimizing the diovascular disease. Thus, improved treatments for modulation of monoaminergic neurotransmission; second, depression are urgently needed. developing medications that act upon neurotransmitter systems other than monoaminergic circuits; and third, using Various forms of psychotherapy, pharmacotherapy, and focal brain stimulation to directly modulate neuronal activity. electroconvulsive therapy (ECT) are currently the most We review the most recent data on novel therapeutic commonly used antidepressant treatments. Serendipitous compounds and their antidepressant potential. These include discoveries and/or a limited understanding of the triple monoamine reuptake inhibitors, atypical antipsychotic neurobiology of depression which largely focused on the augmentation, and dopamine receptor agonists. Compounds monoaminergic neurotransmitter systems led to the de- affecting extra-monoamine neurotransmitter systems include velopment of many of these treatments. As knowledge of CRF1 receptor antagonists, glucocorticoid receptor the neuroscience of depression advances, a number of antagonists, substance P receptor antagonists, NMDA novel targets for antidepressant treatment are being uncov- receptor antagonists, nemifitide, omega-3 fatty acids, and ered and actively investigated. Generally, these treatments melatonin receptor agonists. Focal brain stimulation therapies fall into three major categories: first, medications that include vagus nerve stimulation (VNS), transcranial magnetic optimize the modulation of monoaminergic neurotrans- stimulation (TMS), magnetic seizure therapy (MST), transcranial mitters; second, medications that target nonmonoamine direct current stimulation (tDCS), and deep brain stimulation neurotransmitter and neuromodulatory systems; and third, (DBS). devices that produce focal electrical brain stimulation Addresses targeting brain regions implicated in the pathophysiology 1 Department of Psychiatry and Behavioral Sciences, Emory University of depression. In this review, we discuss these treatments School of Medicine, 2004 Ridgewood Dr, Suite 218, Atlanta, GA 30322, and highlight those that hold the most promise. United States 2 Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle NE, Suite 4000, Atlanta, GA Optimizing monoaminergic modulation 30322, United States The major monoamines include serotonin (5HT), norepi- nephrine (NE), and dopamine (DA). Several randomized, Corresponding author: Rakofsky, Jeffrey J ([email protected]), double-blind, placebo-controlled trials demonstrate that Holtzheimer, Paul E ([email protected]) and Nemeroff, Charles B ([email protected]) medications that modulate monoaminergic neurotrans- mission possess antidepressant efficacy [5]. Such medi- cations include selective serotonin reuptake inhibitors Current Opinion in Chemical Biology 2009, 13:291–302 (SSRIs), 5HT and NE dual-reuptake inhibitors (SNRIs), This review comes from a themed issue on tricyclic/tetracyclic antidepressants (TCAs), monoamine Next-generation therapeutics oxidase inhibitors (MAOIs), and a number of atypical Edited by Karl-Heinz Altmann and Dario Neri antidepressants (e.g. mirtazapine, trazodone, nefazodone, and bupropion). Mechanisms of action for the TCA, SSRI, Available online 6th June 2009 and SNRImedicationsincludeinhibitionofthereuptakeof 1367-5931/$ – see front matter NE and/or 5HT into the presynaptic terminal. MAOIs # 2009 Elsevier Ltd. All rights reserved. inhibit monoamine oxidase, the enzyme which degrades 5HT, NE, and DA in the presynaptic terminal. Mirtaza- DOI 10.1016/j.cbpa.2009.04.617 pine, nefazodone, trazodone, and several atypical antipsy- choticdrugsblockorstimulateoneormorepresynapticand/ or postsynaptic monoamine neurotransmitter receptors. Introduction Depression is prevalent and disabling [1,2]. Despite ad- Following the success of these agents in treating many equate care with currently available treatments, up to depressed patients, interest and research have focused on www.sciencedirect.com Current Opinion in Chemical Biology 2009, 13:291–302 292 Next-generation therapeutics novel approaches to optimize monoaminergic neuro- spective case series suggested that these medications modulation. Considerable effort has been targeted to might augment the action of antidepressant medications DA circuits based on a growing database implicating in the absence of psychosis [25–35]. Two, large randomized DA dysfunction in the pathophysiology of depression placebo-controlled trials have shown that augmentation [6]. Novel treatments in this category include triple with aripiprazole has antidepressant efficacy in patients reuptake inhibitors, atypical antipsychotic augmentation, unresponsive to standard antidepressants [36,37]; in and DA receptor agonists. November 2007, the FDA-approved aripiprazole for this indication. Risperidone may also be effective as an adjunct Triple reuptake inhibitors in SSRI nonresponders as demonstrated in two random- Triple reuptake inhibitors block synaptic reuptake of 5- ized, double-blind, placebo-controlled trials [38,39]andin HT, NE, and DA. Animal studies have demonstrated one trial measuring its antisuicidal effect [40]. Evidence antidepressant-like effects for several of these com- also indicates that quetiapine is effective in the treatment pounds [7–12]. DOV 216 303, one such agent, was found of Major Depressive Disorder (MDD), either alone or in to be safe and tolerable during short-term use in a Phase 1, combination with standard antidepressant medications open-label study [12]. Tesofensine (NS 2330), another [41–45], though one recent study did not demonstrate compound, has shown modest preliminary safety and any such improvement [46]. Quetiapine’s antidepressant efficacy in treating the motor symptoms of Parkinson’s effects are likely due, in part, to the NE reuptake blockade Disease (PD) [13], but clinical data in treating depression and 5HT1A agonism properties of its metabolite, N-desalk- are unavailable. Two double-blind, placebo-controlled ylquetiapine [47]. Olanzapine added to fluoxetine demon- trials of NS 2359, a GlaxoSmithKline compound, which strated superior efficacy in the treatment of MDD when included active comparators (venlafaxine and paroxetine) compared to olanzapine or fluoxetine monotherapy in an showed no significant antidepressant efficacy; the active eight-week double-blind, placebo-controlled trial [48]. comparators were more efficacious than placebo (Glax- However, a single case study showed monotherapy with oSmithKline, data on file). Drug abuse liability and auto- high-dose olanzapine to be effective in the treatment of nomic side effects are two major concerns in the recurrent brief depression [49]. development of DA reuptake inhibitors. The augmentation of antidepressants has also been effec- Atypical antipsychotic augmentation tive in the treatment of bipolar depression as demon- Atypical antipsychotics (risperidone, paliperidone, cloza- strated by the FDA’s approval of an olanzapine– pine, olanzapine, quetiapine, aripiprazole, and ziprasi- fluoxetine combination to treat this condition [50]. Mono- done) exhibit DA D2 receptor occupancy rates of less therapy with the atypical antipsychotic quetiapine was than or equal to 70%. This is in contrast to the older also found to be safe and efficacious in the treatment of ‘typical’ antipsychotics (such as haloperidol and perphe- bipolar depression [51,52], leading to an FDA approval for nazine) that blocked D2 receptors at occupancy rates of this indication in 2006. 90% or more. One or another of the atypical antipsycho- tics have a relatively high affinity for several 5HT recep- Dopamine agonists tors, and possibly glutamate receptors as well [14]; DA D2/D3 receptor agonists include pramipexole and aripiprazole additionally functions as a partial agonist at ropinirole. Two placebo-controlled trials have confirmed the D2 receptor. In the treatment of psychotic disorders, that pramipexole is efficacious, safe, and tolerable in these agents appear to have equivalent efficacy to the patients with bipolar depression [53,54]. Pramipexole older, typical antipsychotics, but with fewer extrapyra- may also be effective in treatment-resistant unipolar midal side effects and lower risk of tardive dyskinesia. depression as demonstrated in an open-label study with However, these agents have been associated with a long-term
Load more

Recommended publications
  • MASCC/ESMO ANTIEMETIC GUIDELINE 2016 with Updates in 2019
    1 ANTIEMETIC GUIDELINES: MASCC/ESMO MASCC/ESMO ANTIEMETIC GUIDELINE 2016 With Updates in 2019 Organizing and Overall Meeting Chairs: Matti Aapro, MD Richard J. Gralla, MD Jørn Herrstedt, MD, DMSci Alex Molassiotis, RN, PhD Fausto Roila, MD © Multinational Association of Supportive Care in CancerTM All rights reserved worldwide. 2 ANTIEMETIC GUIDELINES: MASCC/ESMO These slides are provided to all by the Multinational Association of Supportive Care in Cancer and can be used freely, provided no changes are made and the MASCC and ESMO logos, as well as date of the information are retained. For questions please contact: Matti Aapro at [email protected] Chair, MASCC Antiemetic Study Group or Alex Molassiotis at [email protected] Past Chair, MASCC Antiemetic Study Group 3 ANTIEMETIC GUIDELINES: MASCC/ESMO Consensus A few comments on this guideline set: • This set of guideline slides represents the latest edition of the guideline process. • This set of slides has been endorsed by the MASCC Antiemetic Guideline Committee and ESMO Guideline Committee. • The guidelines are based on the votes of the panel at the Copenhagen Consensus Conference on Antiemetic Therapy, June 2015. • Latest version: March 2016, with updates in 2019. 4 ANTIEMETIC GUIDELINES: MASCC/ESMO Changes: The Steering Committee has clarified some points: 2016: • A footnote clarified that aprepitant 165 mg is approved by regulatory authorities in some parts of the world ( although no randomised clinical trial has investigated this dose ). Thus use of aprepitant 80 mg in the delayed phase is only for those cases where aprepitant 125 mg is used on day 1. • A probable modification in pediatric guidelines based on the recent Cochrane meta-analysis is indicated.
    [Show full text]
  • Antiemetics/Antivertigo Agents
    Antiemetic Agents Therapeutic Class Review (TCR) May 1, 2019 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage or retrieval system without the express written consent of Magellan Rx Management. All requests for permission should be mailed to: Magellan Rx Management Attention: Legal Department 6950 Columbia Gateway Drive Columbia, Maryland 21046 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended to be educational in nature and is intended to be used for informational purposes only. Send comments and suggestions to [email protected]. May 2019 Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2019 Magellan Rx Management. All Rights Reserved. 3 FDA-APPROVED INDICATIONS Drug Manufacturer Indication(s) NK1 receptor antagonists aprepitant capsules generic, Merck In combination with other antiemetic agents for: (Emend®)1 .
    [Show full text]
  • Resolution of Refractory Pruritus with Aprepitant in a Patient With
    Case Report Resolution of refractory pruritus with aprepitant in a patient with microcystic adnexal carcinoma Johanna S Song, MD,ab Hannah Song, BA,a Nicole G Chau, MD,ac Jeffrey F Krane, MD, PhD,ad Nicole R LeBoeuf, MD, MPHabe aHarvard Medical School; bDepartment of Dermatology, Brigham and Women’s Hospital; cCenter for Head and Neck Oncology, Dana-Farber Cancer Institute; dHead and Neck Pathology Service, Brigham and Women’s Hospital; and eCenter for Cutaneous Oncology, Dana-Farber Cancer Institute, all in Boston, Massachusetts ubstance P is an important neurotransmit- biopsied, and the patient was diagnosed with MAC ter implicated in itch pathways.1 After bind- with gross nodal involvement. Laboratory findings ing to its receptor, neurokinin-1 (NK-1), including serum chemistries, blood urea nitrogen, substance P induces release of factors including complete blood cell count, thyroid, and liver func- S 2 histamine, which may cause pruritus. Recent lit- tion were normal. Positron emission tomography- erature has reported successful use of aprepitant, an computed tomography (PET-CT) imaging was NK-1 antagonist that has been approved by the US negative for distant metastases. Food and Drug Administration for the treatment Treatment was initiated with oral aprepitant – of chemotherapy-induced nausea and vomiting, for 125 mg on day 1, 80 mg on day 2, and 80 mg on treatment of pruritus. We report here the case of a day 3 –with concomitant weekly carboplatin (AUC patient with microcystic adnexal carcinoma (MAC) 1.5) and paclitaxel (30 mg/m2) as well as radiation. who presented with refractory pruritus and who had Within hours after the first dose of aprepitant, the rapid and complete resolution of itch after adminis- patient reported a notable cessation in his pruri- tration of aprepitant.
    [Show full text]
  • Evidence-Based Guidelines for Treating Depressive Disorders with Antidepressants
    JOP0010.1177/0269881115581093Journal of PsychopharmacologyCleare et al. 581093research-article2015 BAP Guidelines Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association Journal of Psychopharmacology 2015, Vol. 29(5) 459 –525 for Psychopharmacology guidelines © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881115581093 jop.sagepub.com Anthony Cleare1, CM Pariante2 and AH Young3 With expert co-authors (in alphabetical order): IM Anderson4, D Christmas5, PJ Cowen6, C Dickens7, IN Ferrier8, J Geddes9, S Gilbody10, PM Haddad11, C Katona12, G Lewis12, A Malizia13, RH McAllister-Williams14, P Ramchandani15, J Scott16, D Taylor17, R Uher18 and the members of the Consensus Meeting19 Endorsed by the British Association for Psychopharmacology Abstract A revision of the 2008 British Association for Psychopharmacology evidence-based guidelines for treating depressive disorders with antidepressants was undertaken in order to incorporate new evidence and to update the recommendations where appropriate. A consensus meeting involving experts in depressive disorders and their management was held in September 2012. Key areas in treating depression were reviewed and the strength of evidence and clinical implications were considered. The guidelines were then revised after extensive feedback from participants and interested parties. A literature review is provided which identifies the quality of evidence upon which the recommendations
    [Show full text]
  • HHS Template for Reports, with Instructions
    Texas Vendor Drug Program 1.1 Drug Use Criteria: Substance P/Neurokinin1 Receptor Antagonists Publication History 1. Developed December 2003. 2. Revised September 2020; September 2018; September 2016; May 2015; August 2013; June 2013; September 2011; October 2009; February 2006; January 2006. Notes: Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document. Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Vendor Drug Program formulary coverage. Prepared by: • Drug Information Service, UT Health San Antonio. • The College of Pharmacy, The University of Texas at Austin. 1 1 Dosage [*] Current therapies for chemotherapy-induced nausea/vomiting (CINV) and post- operative nausea and vomiting (PONV) target corticosteroid, dopamine, and serotonin (5-HT3) receptors. In the central nervous system, tachykinins and neurokinins play a role in some autonomic reflexes and behaviors. Aprepitant is a selective human substance P/neurokinin 1 (NK1) antagonist with a high affinity for NK1 receptors and little, if any, attraction for corticosteroid, dopamine, or 5-HT3 receptors. Rolapitant (Varubi®), the newest substance P/NK1 antagonist, is FDA- approved to prevent delayed CINV with initial and repeat chemotherapy courses including, but not limited to, highly emetogenic chemotherapy in adults. Combination therapy including netupitant, a substance P/NK1 antagonist and palonosetron, a selective 5-HT3 receptor antagonist (Akynzeo®), is now available to prevent acute and delayed CINV with initial and repeat chemotherapy courses including, but not limited to, highly emetogenic chemotherapy in adults.
    [Show full text]
  • Gastroparesis: 2014
    GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #1 Richard W. McCallum, MD, FACP, FRACP (Aust), FACG Status of Pharmacologic Management of Gastroparesis: 2014 Richard W. McCallum Joseph Sunny, Jr. Gastroparesis is characterized by delayed gastric emptying without mechanical obstruction of the gastric outlet or small intestine. The main etiologies are diabetes, idiopathic and post- gastric and esophageal surgical settings. The management of gastroparesis is challenging due to a limited number of medications and patients often have symptoms, which are refractory to available medications. This article reviews current treatment options for gastroparesis including adverse events and limitations as well as future directions in pharmacologic research. INTRODUCTION astroparesis is a syndrome characterized by documented gastroparesis are increasing.2 Physicians delayed emptying of gastric contents without have both medical and surgical approaches for these Gmechanical obstruction of the stomach, pylorus or patients (See Figure 1). Medical therapy includes both small bowel. Patients can present with nausea, vomiting, prokinetics and antiemetics (See Table 1 and Table 2). postprandial fullness, early satiety, pressure, fullness The gastroparesis population will grow as diabetes and abdominal distension. In addition, abdominal pain increases and new therapies will be required. What located in the epigastrium, and distinguished from the do we know about the size of the gastroparetic term discomfort, is increasingly being recognized population? According to a study from the Mayo Clinic as an important symptom. The main etiologies of group surveying Olmsted County in Minnesota, the gastroparesis are diabetes, idiopathic, and post gastric risk of gastroparesis in Type 1 diabetes mellitus was and esophageal surgeries.1 Hospitalizations from significantly greater than for Type 2.
    [Show full text]
  • Initial Public Comment for Aprepitant for Chemotherapy-Induced Emesis CAG-00248N July 6 – August 6, 2004
    Initial Public Comment for Aprepitant for Chemotherapy-Induced Emesis CAG-00248N July 6 – August 6, 2004 Commenter: Duncan, Sariah, RN, BSN, OCN Organization: Date: August 2, 2004 Comment: Please Do Not Limit Anti-Emetic Coverage!! I don't think Emend should be considered full replacement for other covered treatments for chemotherapy induced emesis. On the few patients who it was prescribed to in our clinic, it did not always work well. We find that we still have to give the patient IV anti-emetics, even if they took Emend, because they still throw up. ------------------------------------------------------------------------------------------------------- Commenter: Takahashi, Gary Organization: Oregon Hematology Oncology Association Date: August 6, 2004 Comment: In my experience, Emend (aprepitant) is useful only as an adjunct to other antiemetics to prevent delayed-onset nausea and vomiting. It is only mildly effective when given alone, and must be combined with more potent anti-emetics to control acute-onset nausea. I recommend against using Emend as an oral substitute for drugs such as granisetron or palonosetron. -------------------------------------------------------------------------------------------------------- Commenter: D’Emanuele, Ross Organization: Dorsey & Whitney, LLP Date: August 6, 2004 Comment: Public Comment Offered in Response to CMS’ National Coverage Analysis (NCA) Titled “Aprepitant for Chemotherapy-Induced Emesis” (CAG-00248N) POSITION Oral EMEND® is not a replacement for any current commercially available intravenous antiemetic in the United States. Therefore, it is not appropriate to reimburse it as a Medicare Part B benefit. EMEND needs to be administered in conjunction with a 5-HT3 receptor antagonist and is not stand alone therapy. It does not function as a prodrug or have an IV equivalent.
    [Show full text]
  • The Significance of NK1 Receptor Ligands and Their Application In
    pharmaceutics Review The Significance of NK1 Receptor Ligands and Their Application in Targeted Radionuclide Tumour Therapy Agnieszka Majkowska-Pilip * , Paweł Krzysztof Halik and Ewa Gniazdowska Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland * Correspondence: [email protected]; Tel.: +48-22-504-10-11 Received: 7 June 2019; Accepted: 16 August 2019; Published: 1 September 2019 Abstract: To date, our understanding of the Substance P (SP) and neurokinin 1 receptor (NK1R) system shows intricate relations between human physiology and disease occurrence or progression. Within the oncological field, overexpression of NK1R and this SP/NK1R system have been implicated in cancer cell progression and poor overall prognosis. This review focuses on providing an update on the current state of knowledge around the wide spectrum of NK1R ligands and applications of radioligands as radiopharmaceuticals. In this review, data concerning both the chemical and biological aspects of peptide and nonpeptide ligands as agonists or antagonists in classical and nuclear medicine, are presented and discussed. However, the research presented here is primarily focused on NK1R nonpeptide antagonistic ligands and the potential application of SP/NK1R system in targeted radionuclide tumour therapy. Keywords: neurokinin 1 receptor; Substance P; SP analogues; NK1R antagonists; targeted therapy; radioligands; tumour therapy; PET imaging 1. Introduction Neurokinin 1 receptor (NK1R), also known as tachykinin receptor 1 (TACR1), belongs to the tachykinin receptor subfamily of G protein-coupled receptors (GPCRs), also called seven-transmembrane domain receptors (Figure1)[ 1–3]. The human NK1 receptor structure [4] is available in Protein Data Bank (6E59).
    [Show full text]
  • 1 Advances in Therapeutic Peptides Targeting G Protein-Coupled
    Advances in therapeutic peptides targeting G protein-coupled receptors Anthony P. Davenport1Ϯ Conor C.G. Scully2Ϯ, Chris de Graaf2, Alastair J. H. Brown2 and Janet J. Maguire1 1Experimental Medicine and Immunotherapeutics, Addenbrooke’s Hospital, University of Cambridge, CB2 0QQ, UK 2Sosei Heptares, Granta Park, Cambridge, CB21 6DG, UK. Ϯ Contributed equally Correspondence to Anthony P. Davenport email: [email protected] Abstract Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled receptors (GPCRs) — nearly fifty GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology, and more than 10 potentially first- in-class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide-binding GPCRs. Increasingly, novel strategies are being employed to develop both agonists and antagonists, and both to introduce chemical novelty and improve drug-like properties. Pharmacodynamic improvements are evolving to bias ligands to activate specific downstream signalling pathways in order to optimise efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma-half life have been revolutionary. Here, we discuss the current status of peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties. Introduction G protein-coupled receptors (GPCRs) mediate a wide range of signalling processes and are targeted by one third of drugs in clinical use1. Although most GPCR-targeting therapeutics are small molecules2, the endogenous ligands for many GPCRs are peptides (comprising 50 or fewer amino acids), which suggests that this class of molecule could be therapeutically useful.
    [Show full text]
  • Antidepressant-Like Effects of the Vasopressin V1b Receptor Antagonist SSR149415 in the Flinders Sensitive Line Rat
    Pharmacology, Biochemistry and Behavior 82 (2005) 223 – 227 www.elsevier.com/locate/pharmbiochembeh Antidepressant-like effects of the vasopressin V1b receptor antagonist SSR149415 in the Flinders Sensitive Line rat David H. Overstreet a,*, Guy Griebel b a Department of Psychiatry and Bowles Center for Alcohol Studies, CB 7178, 429 Taylor Bldg., University of North Carolina, Chapel Hill, NC 27599-7178, USA b Sanofi-Aventis, Avenue P.V. Couturier, 92220 Bagneux, France Received 13 April 2005; received in revised form 18 July 2005; accepted 18 July 2005 Abstract There is an increased interest in the potential of vasopressin receptor antagonists as antidepressants because of the involvement of vasopressin in stress-related behavioral changes. The present study sought to provide confirmatory evidence for the antidepressant-like effects of the selective vasopressin V1b receptor antagonist SSR149415, which had been previously demonstrated in a variety of animal models. The Flinders Sensitive Line (FSL) rat, a selectively bred animal model of depression, was chronically treated for 14 days with SSR149415 (1, 10, and 30 mg/kg), vehicle, or desipramine (5 mg/kg) as a positive control. Approximately 22–24 h after the last treatment, the rats were exposed to a single 5-min session in a cylinder containing 25 -C water and immobility was recorded. A control group of Flinders Resistant Line (FRL) rats was included as a reference group as well as one treated with 10 mg/kg SSR149415. Vehicle-treated FSL rats exhibited much more immobility than the FRL rats, and desipramine-treated FSL rats had much lower scores, as expected. Treatment with SSR149415 reduced immobility in the FSL rats at all doses, but only the higher doses reduced it such that they were no longer different from the FRL rats.
    [Show full text]
  • Ep 2522664 B1
    (19) TZZ _T (11) EP 2 522 664 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 401/04 (2006.01) C07D 413/04 (2006.01) 12.04.2017 Bulletin 2017/15 A61K 31/4545 (2006.01) (21) Application number: 12169655.3 (22) Date of filing: 29.06.2005 (54) Piperidine derivatives as NK1 antagonists Piperidinderivate als NK1-Antagonisten Dérivés de pipéridine en tant qu’ antagonistes NK1 (84) Designated Contracting States: • Wrobleski, Michelle Laci AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Whitehouse Station, NJ New Jersey 08889 (US) HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR • Rao, Ashwin U. Designated Extension States: Avenel, NJ New Jersey 07001 (US) AL BA HR LV MK YU • Wang, Cheng King of Prussia, PA Pennsylvania 19406 (US) (30) Priority: 01.07.2004 US 584502 P • Shah, Sapna S. Westampton, NJ New Jersey 08060 (US) (43) Date of publication of application: 14.11.2012 Bulletin 2012/46 (74) Representative: Simpson, Tobias Rutger Mathys & Squire LLP (62) Document number(s) of the earlier application(s) in The Shard accordance with Art. 76 EPC: 32 London Bridge Street 05787862.1 / 1 799 666 London SE1 9SG (GB) (73) Proprietor: OPKO Health, Inc. (56) References cited: Miami, FL 33137 (US) WO-A-03/042173 WO-A-03/051840 (72) Inventors: • WU X ET AL: "Stereoselective Transformation of • Palani, Anandan 2H-1,4-Oxazin-2-ones into 2,(2),5,5-Tri- and Bridgewater, NJ New Jersey 08807 (US) Tetrasubstituted Analogues of • Shih, Neng-Yang cis-5-Hydroxy-2-piperidinemethanol and Warren, NJ New Jersey 07059 (US) cis-5-Hydroxy-6-oxo-2-piperidi necarboxylic • Huang, Xianhai Acid", TETRAHEDRON, ELSEVIER SCIENCE Warren, NJ New Jersey 07059 (US) PUBLISHERS, AMSTERDAM, NL, vol.
    [Show full text]
  • Datasheet Inhibitors / Agonists / Screening Libraries a DRUG SCREENING EXPERT
    Datasheet Inhibitors / Agonists / Screening Libraries A DRUG SCREENING EXPERT Product Name : Nemifitide diTFA Catalog Number : TP1127 CAS Number : 204992-09-6 Molecular Formula : C37H45F7N10O10 Molecular Weight : 922.80 Description: Nemifitide (diTFA) is is a synthetic pentapeptide antidepressant with a potential for rapid onset of action. Nemifitide (diTFA) is a peptide analog of melanocyte-inhibiting factor (MIF). Storage: 2 years -80°C in solvent; 3 years -20°C powder; In vitro Activity In-vitro studies indicate that both nemifitide and its active metabolite (M1) bind at micromolar concentrations to several receptors including the 5-HT2A, 5-HT2C, melanocortin MC4, MC5 and bombesin[3]. In vivo Activity Nemifitide (0.3 mg/kg; IP; daily; for 14 days) significantly increases swimming in the FSL rats after just 5 days of treatment and has long-lasting effect[2]. Nemifitide (0.0125-15.0 mg/kg) significantly increases swimming in the FSL rats at both low (0.025- 0.3 mg/kg) and high (3.0-15.0 mg/kg) doses but not at intermediate (0.4-2.4 mg/kg) doses[2]. Reference 1. Kelly JP, et al. The effect of treatment with a new antidepressant, INN 00835, on platelet serotonin uptake in depressed patients. J Affect Disord. 1999 Oct;55(2-3):231-5. 2. Overstreet DH, et al. Antidepressant-like effects of a novel pentapeptide, nemifitide, in an animal model of depression. Psychopharmacology (Berl). 2004 Sep;175(3):303-9. 3. Montgomery SA, et al. Efficacy and safety of 30 mg/d and 45 mg/d nemifitide compared to placebo in major depressivedisorder.
    [Show full text]