AVN-322 is a safe orally bio-available potent and highly selective antagonist of 5-HT6R with demonstrated ability to improve impaired memory in animal models

Current Alzheimer Research

Volumn 14, Issue 3, 2017, Pages 268-294

  Ivachtchenko, Alexandre V ^a,b   Ivanenkov, Yan A ^c,e   Veselov, Mark S ^c,e   Okun, I M ^d  

^a Alla Chem LLC   (United States)

^b Avineuro Pharmaceuticals Inc   (United States)

^c MOSCOW INSTITUTE OF PHYSICS AND TECHNOLOGY   (Russian Federation)

^d CHEMDIV INC   (United States)

^e MOSCOW STATE UNIVERSITY   (Russian Federation)

Author keywords

5 HT6 antagonist; Alzheimer s; CNS diseases; Cognition; Memory

Indexed keywords

ADENOSINE TRIPHOSPHATASE; ANTIDEPRESSANT AGENT; ANXIOLYTIC AGENT; AVN 322; CYTOCHROME; DIZOCILPINE; KETOPROFEN; METHOTREXATE; NEUROLEPTIC AGENT; NOOTROPIC AGENT; POTASSIUM CHANNEL HERG; PROPRANOLOL; SCOPOLAMINE; SEROTONIN 6 ANTAGONIST; UNCLASSIFIED DRUG; FUSED HETEROCYCLIC RINGS; N,7-DIMETHYL-3-(PHENYLSULFONYL)-6,7,8,9-TETRAHYDROPYRAZOLO(1,5-A)PYRIDO(3,4-E)PYRIMIDIN-2-AMINE; SEROTONIN 6 RECEPTOR; SEROTONIN ANTAGONIST; SEROTONIN RECEPTOR;

ALZHEIMER DISEASE; AMNESIA; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIDEPRESSANT ACTIVITY; AQUEOUS SOLUTION; AREA UNDER THE CURVE; ARTICLE; BEAGLE; BINDING AFFINITY; BLOOD BRAIN BARRIER; CACO-2 CELL LINE; CHINCHILLA RABBIT; COGNITIVE DEFECT; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG STABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; ELEVATED PLUS MAZE TEST; FORCED SWIM TEST; GENOTOXICITY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LD50; MAXIMUM PLASMA CONCENTRATION; MORRIS WATER MAZE TEST; MOUSE; MUTAGENICITY; NONHUMAN; NOVEL OBJECT RECOGNITION TEST; PASSIVE AVOIDANCE TEST; PHARMACEUTICAL CARE; PLASMA; PLASMA PROTEIN BINDING; PRECLINICAL STUDY; PRIORITY JOURNAL; RAT; RHESUS MONKEY; SCHIZOPHRENIA; TAIL SUSPENSION TEST; TIME TO MAXIMUM PLASMA CONCENTRATION; ANIMAL; DISEASE MODEL; DOG; DRUG ABSORPTION; FEMALE; HEK293 CELL LINE; INTRAVENOUS DRUG ADMINISTRATION; MALE; MEMORY DISORDERS; METABOLISM; ORAL DRUG ADMINISTRATION; SPRAGUE DAWLEY RAT; TUMOR CELL LINE; WISTAR RAT;

ADMINISTRATION, INTRAVENOUS; ADMINISTRATION, ORAL; ALZHEIMER DISEASE; ANIMALS; ANTIPSYCHOTIC AGENTS; CELL LINE, TUMOR; DISEASE MODELS, ANIMAL; DOGS; DRUG EVALUATION, PRECLINICAL; FEMALE; HEK293 CELLS; HETEROCYCLIC COMPOUNDS, 3-RING; HUMANS; MACACA MULATTA; MALE; MEMORY DISORDERS; MICE; NOOTROPIC AGENTS; PERITONEAL ABSORPTION; RATS, SPRAGUE-DAWLEY; RATS, WISTAR; RECEPTORS, SEROTONIN; SCHIZOPHRENIA; SEROTONIN ANTAGONISTS;

EID: 85013980947     PISSN: 15672050     EISSN: 18755828     Source Type: Journal    
DOI: None     Document Type: Article

References (104)

1. World Health Organization. WHO Dementia. Available from:http: //www.who.int/mediacentre/factsheets/fs362/en/
2. Ghezzi L, Scarpini E, Galimberti D. Disease-modifying drugs in Alzheimer’s disease. Drug Des Dev Ther 7: 1471-8 (2013).
3. Bowen DM, Francis PT, Pangalos MN, Stephens PH, Procter AW, Lewis P. Treatment strategies for Alzheimer’s disease. Lancet 339 (8785): 132-3 (1992).
4. Whitehouse PJ, Martino AM, Antuono PG, Lowenstein PR, Coyle JT, Price DL. Nicotinic acetylcholine binding sites in Alzheimer’s disease. Brain Res 371 (1): 146-51 (1986).
5. Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M, Wimo A, et al. Alzheimer’s disease: clinical trials and drug development. Lancet Neurol 9 (7): 702-716 (2010).
6. Thomas SJ, Grossberg GT. Memantine: a review of studies into its safety and efficacy in treating Alzheimer’s disease and other dementias. Clin Interv Aging 4: 367-377 (2009).
7. Geldenhuys WJ, Van der Schyf CJ. The serotonin 5-HT6 receptor: a viable drug target for treating cognitive deficits in Alzheimer’s disease. Expert Rev Neurother 9 (7): 1073-1085 (2009).
8. Geldenhuys WJ, Van der Schyf CJ. Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer’s disease. Curr Top Med Chem 8 (12): 1035-1048 (2008).
9. Glennon RA, Siripurapu U, Roth BL, Kolanos R, Bondarev ML, Sikazwe D, et al. The medicinal chemistry of 5-HT6 receptor ligands with a focus on arylsulfonyltryptamine analogs. Curr Top Med Chem 10 (5): 579-595 (2010).
10. Ivachtchenko A V., Lavrovsky Y, Okun I. AVN-101: A multitarget drug candidate for the treatment of CNS disorders. J Alzheimer’s Dis 53 (2): 583-620 (2016).
11. Geldenhuys WJ, Van der Schyf CJ. Role of serotonin in Alzheimer’s disease: a new therapeutic target? CNS Drugs 25 (9): 765-781 (2011).
12. Marazziti D, Rutigliano G, Dell’Osso MC, Baroni S, Dell’Osso L. The 5-HT6 receptor antagonism approach in Alzheimer’s disease. Drugs Future 39 (2): 133-140 (2014).
13. Schneider L. Idalopirdine for Alzheimer’s disease: written in the stars. Lancet Neurol 13 (11): 1063-1065 (2014).
14. NCT02585934. Study Evaluating RVT-101 in Subjects With Mild to Moderate Alzheimer’s Disease on Donepezil Treatment: MINDSET Study. Available from: https://clinicaltrials.gov/ct2/ show/record/NCT02585934
15. RVT-101-Axovant Sciences. Available from: http: //axovant.com/ rvt-101/clinical-trial/mindset/
16. RVT-101-ALZFORUM. Available from: http: //www.alzforum. org/therapeutics/rvt-101
17. NCT01712074. Study Evaluating The Safety And Efficacy Of PF-05212377 Or Placebo In Subjects With Alzheimer’s Disease With Existing Neuropsychiatric Symptoms On Donepezil. Available from: https://clinicaltrials.gov/ct2/show/NCT01712074
18. Bell J, Baird-Bellaire S, Leil T, Comery T, Plotka A, Antinew J, et al. Single-and multiple-dose safety, tolerability and pharmacokinetics of a Novel 5HT6 receptor full antagonist (SAM-760) for the treatment of the symptoms of Alzheimer’s disease in healthy young adults and elderly subjects. Alzheimer’s Dement 7 (4): S778 P4-214 (2011).
19. PF-05212377. Available from: http: //www.alzforum.org/ therapeutics/pf-05212377
20. Nirogi R, Kambhampati R, Shinde A, Kandikere V, Mudigonda K, Bhyrapuneni G, et al. SUVN-502: A safe, potent, selective, brain penetrant and orally active 5-HT6 receptor antagonist-first in human clinical phase-1 study. Alzheimer’s Dement 5 (4): P250 (2009).
21. Avineuro Completed Phase II Clinical Study Of AVN-211, A Selective 5-HT6 Receptor Antagonist. Available from: http: //www.avineuro.com/avineuro-completed-phase-ii-clinicalstudy-of-avn-211-a-selective-5-ht6-receptor-antagonist/
22. Ivachtchenko AV, Golovina ES, Kadieva MG, Kysil VM, Mitkin OD, Vorobiev AA, et al. Antagonists of 5-HT6 receptors. Substituted 3-(phenylsulfonyl) pyrazolo[1, 5-a]pyrido[3, 4-e]pyrimidines and 3-(phenylsulfonyl) pyrazolo[1, 5-a]pyrido[4, 3-d]pyrimidines—Synthesis and “structure–activity” relationship. Bioorg Med Chem Lett 22 (13): 4273-4280 (2012).
23. Okun I, Tkachenko SE, Khvat A, Mitkin O, Kazey V, Ivachtchenko AV. From anti-allergic to anti-Alzheimer’s: Molecular pharmacology of Dimebon. Curr Alzheimer Res 7 (2): 97-112 (2010).
24. S9 Stability Assay-Cyprotex. Available from: http: //www.cyprotex.com/admepk/in-vitro-metabolism/s9-stability
25. ThermoFisher Scientific. RED Device Inserts. Available from: https://tools.thermofisher.com/content/sfs/manuals/MAN0011571_ RED_Device:Insert_UG.pdf
26. ThermoFisher Scientific. CyP450 Biochemical Screening Kits Catalog | Thermo Fisher Scientific. Available from: https://www.thermofisher.com/search/results?query=CyP450+Bioc hemical+Screening+Kits&resultPage=1&resultsPerPage=15&autoc omplete=true
27. AAALAC. Guide for the Care and Use of Laboratory Animals. Available from: https://aaalac.org/resources/theguide.cfm
28. Nirogi R, Kandikere V, Mudigonda K, Bhyrapuneni G, Muddana N, Saralaya R, et al. A simple and rapid method to collect the cerebrospinal fluid of rats and its application for the assessment of drug penetration into the central nervous system. J Neurosci Meth 178 (1): 116-119 (2009).
29. Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance. (1996). Available from: http: //www.fda.gov/cder/ guidance/index.htm
30. Walf AA, Frye CA. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2 (2): 322-328 (2007).
31. Castagné V, Moser P, Porsolt RD. Behavioral Assessment of Antidepressant Activity in Rodents. In: Buccafusco JJ, Ed. Methods of Behavior Analysis in Neuroscience. 2nd ed. Boca Raton (FL): CRC Press (2009).
32. Graham JH, Jerry J. Buccafusco. Inhibitory avoidance behavior and memory assessment. In: Buccafusco JJ, Ed. Methods of behavior analysis in neuroscience. Boca Raton (FL): CRC Press pp. 153-163 (2001).
33. Vorhees C V, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1 (2): 848-858 (2006).
34. Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res 31 (1): 47-59 (1988).
35. Klinkenberg I, Blokland A. The validity of scopolamine as a pharmacological model for cognitive impairment: a review of animal behavioral studies. Neurosci Biobehav Rev 34 (8): 1307-1350 (2010).
36. Brown JW, Rueter LE, Zhang M. Predictive validity of a MK-801-induced cognitive impairment model in mice: implications on the potential limitations and challenges of modeling cognitive impairment associated with schizophrenia preclinically. Prog Neuropsychopharmacol Biol Psychiatry 49: 53-62 (2014).
37. Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Proc 13 (2): 93-110 (2012).
38. Briones TL, Hala Darwish. Vitamin D mitigates age-related cognitive decline through the modulation of pro-inflammatory state and decrease in amyloid burden. J Neuroinflammation 9 (1): 244-256 (2012).
39. Mällo T, Alttoa A, Kõiv K, Tõnissaar M, Eller M, Harro J. Rats with persistently low or high exploratory activity: behaviour in tests of anxiety and depression, and extracellular levels of dopamine. Behav Brain Res 177 (2): 269-281 (2007).
40. The Salmonella/E. coli Mutagenicity Test or Ames Test-NTP. Available from: http: //ntp.niehs.nih.gov/testing/types/genetic/ invitro/sa/index.html
41. Ames BN, Lee FD, Durston WE. An improved bacterial test system for the detection and classification of mutagens and carcinogens. Proc Natl Acad Sci USA 70 (3): 782-786 (1973).
42. Taylor EW. The Mechanism of Colchicine Inhibition of Mitosis. I. Kinetics of Inhibition and the Bindingof H3-Colchicine. J Cell Biol 25 (1): 145-160 (1965).
43. Preston RJ, Dean BJ, Galloway S, Holden H, McFee AF, Shelby M, et al. Mammalian in vivo cytogenetic assays Analysis of chromosome aberrations in bone marrow cells. Mutat Res Toxicol 189 (2): 157-165 (1987).
44. Ivachtchenko AV, Ivanenkov YA. Small molecule 5-HT6R ligands: a comprehensive insight into their selectivity and activity. Curr Bioact Compd 9 (1): 64-100 (2013).
45. Arnt J, Bang-Andersen B, Grayson B, Bymaster FP, Cohen MP, DeLapp NW, et al. Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int J Neuropsychopharmacol 13 (8): 1021-1033 (2010).
46. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, et al. Evidence for possible involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications. Circulation 102 (23): 2836-2841 (2000).
47. Hofmann C, Penner U, Dorow R, Pertz HH, Jähnichen S, Horowski R, et al. Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis. Clin Neuropharmacol 29 (2): 8086 (2006).
48. Shyu K-G. Serotonin 5-HT2B receptor in cardiac fibroblast contributes to cardiac hypertrophy: a new therapeutic target for heart failure? Circ Res 104 (1): 1-3 (2008).
49. Moss N, Choi Y, Cogan D, Flegg A, Kahrs A, Loke P, et al. A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties. Bioorg Med Chem Lett 19 (8): 2206-2210 (2009).
50. Press B. Optimization of the Caco-2 permeability assay to screen drug compounds for intestinal absorption and efflux. Methods Mol Biol 763: 139-154 (2011).
51. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, et al. Rational Use of in Vitro P-glycoprotein Assays in Drug Discovery. J Pharmacol Exp Ther 299 (2): 620-628 (2011).
52. Johnson EA, Fox JL, Azzaro AJ. The anxiolytic serotonin 5-HT1A receptor agonists buspirone, ipsapirone and gepirone are inhibitors of tyrosine hydroxylation in rat striatum. Behav Brain Res 73 (1–2): 331-335 (1996).
53. Garattini S, Caccia S, Mennini T. Notes on buspirone’s mechanisms of action. J Clin Psychiatry 43 (12 Pt 2): 19-24 (1982).
54. Lorazepam-Medical Countermeasures Database-CHEMM. U.S.Department of Helath & Human Services. Available from: https://chemm.nlm.nih.gov/countermeasure_lorazepam.htm#eb
55. Fluoxetine. DrugBank. Available from: http: //www.drugbank.ca/ drugs/DB00472
56. Desipramine. DrugBank. Available from: http: //www.drugbank.ca/ drugs/DB01151
57. Tacrine. DrugBank. Available from: http: //www.drugbank.ca/ drugs/DB00382
58. Donepezil. DrugBank. Available from: http: //www.drugbank.ca/ drugs/DB00843
59. Memantine. DrugBank. Available from: http: //doi.wiley.com/ 10.1113/jphysiol.2009.176297
60. Dodart JC, Mathis C, Ungerer A. NeuroReport. Neuroreport. 8 (5): 1173–1178 (1997).
61. Bubeníková-Valesová V, Horácek J, Vrajová M, Höschl C. Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev 32 (5): 1014-1023 (2008).
62. Piracetam-Nootropic Review of Effects, Dosage, and More. Braintropic. Available from: http: //www.braintropic.com/ nootropics/piracetam/
63. Braff D, Stone C, Callaway E, Geyer M, Glick I, Bali L. Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology 15 (4): 339-343 (1978).
64. Swerdlow NR, Geyer MA, Braff DL. Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl) 156 (2-3): 194-215 (2001).
65. Kumari V, Sharma T. Effects of typical and atypical antipsychotics on prepulse inhibition in schizophrenia: a critical evaluation of current evidence and directions for future research. Psychopharmacology (Berl) 162 (2): 97-101 (2002).
66. Ludewig S, Geyer MA, Ramseier M, Vollenweider FX, Rechsteiner E, Cattapan-Ludewig K. Information-processing deficits and cognitive dysfunction in panic disorder. J Psychiatry Neurosci 30 (1): 37-43 (2005).
67. Cadenhead KS, Geyer MA, Braff DL. Impaired startle prepulse inhibition and habituation in patients with schizotypal personality disorder. Am J Psychiatry 150 (12): 1862-1867 (1993).
68. Swerdlow NR, Benbow CH, Zisook S, Geyer MA, Braff DL. A preliminary assessment of sensorimotor gating in patients with obsessive compulsive disorder. Biol Psychiatry 33 (4): 298-301 (1993).
69. Swerdlow NR, Paulsen J, Braff DL, Butters N, Geyer MA, Swenson MR. Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington’s disease. J Neurol Neurosurg Psychiatry 58 (2): 192-200 (1995).
70. Ornitz EM, Hanna GL, de Traversay J. Prestimulation-induced startle modulation in attention-deficit hyperactivity disorder and nocturnal enuresis. Psychophysiology 29 (4): 437-451 (1992).
71. Swerdlow NR, Zinner S, Hartston H, Filion D, Magulac M. Central inhibitory deficits in OCD and tourette syndrome. Biol Psychiatry 35 (9): 664 (1994).
72. Castellanos FX, Fine EJ, Kaysen D, Marsh WL, Rapoport JL, Hallett M. Sensorimotor gating in boys with Tourette’s syndrome and ADHD: preliminary results. Biol Psychiatry 39 (1): 33-41 (1996).
73. Caine SB, Geyer MA, Swerdlow NR. Hippocampal modulation of acoustic startle and prepulse inhibition in the rat. Pharmacol Biochem Behav 43 (4): 1201-1208 (1992).
74. Swerdlow NR. Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatry 51 (2): 139-154 (1994).
75. Swerdlow NR, Geyer MA. Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr Bull 24 (2): 285-301 (1998).
76. Malmberg, Mikaels, Mohell N. Agonist and inverse agonist activity at the dopamine D3 receptor measured by guanosine 5’--gammathio-triphosphate--35S-binding. J Pharmacol Exp Ther 285 (1): 119-126 (1998).
77. Leysen JE, Janssen PM, Gommeren W, Wynants J, Pauwels PJ, Janssen PA. In vitro and in vivo receptor binding and effects on monoamine turnover in rat brain regions of the novel antipsychotics risperidone and ocaperidone. Mol Pharmacol 41 (3): 494-508 (1992).
78. Kalish LA. Efficient design for estimation of median lethal dose and quantal dose-response curves. Biometrics 46 (3): 737-748 (1990).
79. Matsuzawa T, Hayashi Y, Nomura M, Unno T, Igarashi T, Furuya T, et al. A survey of the values of clinical chemistry parameters obtained for a common rat blood sample in ninety-eight Japanese laboratories. J Toxicol Sci 22 (1): 25-44 (1997).
80. Johnson-Delaney CA, Harrison LR. Exotic Animal Companion Medicine Handbook for Veterinarians. Lake Worth, FL: Wingers Pub 1996.
81. Giknis MLA, Clifford CB. Clinical Laboratory Parameters for Crl: WI (Han) Rats. (2008). Available at: www.crivel.com
82. Medirabbit. Available from: http: //www.medirabbit.com/EN/ Hematology/blood_chemistry.htm
83. Martin JF, Slater DN, Kishk YT, Trowbridge EA. Platelet and megakaryocyte changes in cholesterol-induced experimental atherosclerosis. Arteriosclerosis 5 (6): 604-612 (1985).
84. Cattaneo M, Chahil A, Somers D, Kinlough-Rathbone RL, Packham MA, Mustard JF. Effect of aspirin and sodium salicylate on thrombosis, fibrinolysis, prothrombin time, and platelet survival In rabbits with indwelling aortic catheters. Blood 61 (2): 353-361 (1983).
85. Nielsen VG. The Detection of Changes in Heparin Activity in the Rabbit: A comparison of anti-xa activity, thrombelastography, activated partial thromboplastin time, and activated coagulation time. Anesth Analg 95 (6): 1503-1506 (2002).
86. Glennon RA. Higher-End Serotonin Receptors: 5-HT5, 5-HT6, and 5-HT7. J Med Chem 46 (14): 2795-2812 (2003).
87. Ivachtchenko A V, Ivanenkov YA. 5HT (6) receptor antagonists: a patent update. Part 1. Sulfonyl derivatives. Exp Opin Ther Pat 22 (8): 917-964 (2012).
88. Ivachtchenko A V, Ivanenkov YA, Skorenko A V. 5-HT (6) receptor modulators: a patent update. Part 2. Diversity in heterocyclic scaffolds. Exp Opin Ther Pat 22 (10): 1123-1168 (2012).
89. Rossé G, Schaffhauser H. 5-HT6 receptor antagonists as potential therapeutics for cognitive impairment. Curr Top Med Chem 10 (2): 207-221 (2010).
90. Schaffhauser H, Mathiasen JR, DiCamillo A, Huffman MJ, Lu LD, McKenna BA, et al. Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities. Biochem Pharmacol 78 (8): 1035-1042 (2009).
91. Wesołowska A. Potential role of the 5-HT6 receptor in depression and anxiety: an overview of preclinical data. Pharmacol Rep 62 (4): 564-577 (2010).
92. Wesołowska A, Nikiforuk A. Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression. Neuropharmacology 52 (5): 1274-1283 (2007).
93. Ivachtchenko AV, Lavrovsky Y, Ivanenkov YA. AVN-211, novel and highly selective 5-HT6 receptor small molecule antagonist, for the treatment of Alzheimer’s disease. Mol Pharm 13 (3): 945-963 (2016).
94. Upton N, Chuang TT, Hunter AJ, Virley DJ. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease. Neurotherapeutics 5 (3): 458-469 (2008).
95. Benhamú B, Martín-Fontecha M, Vázquez-Villa H, Pardo L, López-Rodríguez ML. Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer’s disease. J Med Chem 57 (17): 7160-7181 (2014).
96. Johnson CN, Ahmed M, Miller ND. 5-HT6 receptor antagonists: prospects for the treatment of cognitive disorders including dementia. Curr Opin Drug Discov Dev 11 (5): 642-654 (2008).
97. Liem-Moolenaar M, Rad M, Zamuner S, Cohen AF, Lemme F, Franson KL, et al. Central nervous system effects of the interaction between risperidone (single dose) and the 5-HT6 antagonist SB742457 (repeated doses) in healthy men. Br J Clin Phayrmacol 71 (6): 907-916 (2011).
98. Nikiforuk A, Kos T, Wesołowska A. The 5-HT6 receptor agonist EMD 386088 produces antidepressant and anxiolytic effecyts in rats after intrahippocampal administration. Psychopharmacology (Berl) 217 (3): 411-418 (2011).
99. Jaystrzębska-Więsek M, Siwek A, Partyka A, Szewczyk B, Sowa-Kućma M, Wasik A, et al. Antidepressant-like activity of EyMD 386088, a 5-HT6 receptor partial agonist, following systemic acute and chronic administration to rats. Naunyn Schmiedebergs Arch Pharmacol 388 (10): 1079-1088 (2015).
100. Jastrzębska-Więsek M, Siwek A, Partyka A, Kubacka M, Mogilski S, Wasik A, et al. Pharmacological evaluation of the anxiolytic-like effects of EMD 386088, a partial 5-HT6 receptor agonist, in the rat elevated plus-maze and Vogel conflict tests. Neuropharmacology 85: 253-262 (2014).
101. Jastrzębska-Więsek M, Siwek A, Partyka A, Antkiewicz-Michaluk L, Michaluk J, Romańska I, et al. Study of a mechanism responsible for potential antidepressant activity of EMD 386088, a 5-HT6 partial agonist in rats. Naunyn Schmiedebergs Arch Pharmacol 389 (8): 839-849 (2016).
102. Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156 (2-3): 117-154 (2001).
103. Haloperidol. DrugBank. Available from: http: //www.drugbank.ca/ drugs/DB00502
104. Fijał K, Popik P, Nikiforuk A. Co-administration of 5-HT6 receptor antagonists with clozapine, risperidone, and a 5-HT2A receptor antagonist: effects on prepulse inhibition in rats. Psychopharmacology (Berl) 231 (1): 269-281 (2014).