Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission
Gretchen L Snyder, Kimberly E Vanover, Hongwen Zhu, Diane B Miller, James P O'Callaghan, John Tomesch, Peng Li, Qiang Zhang, Vaishnav Krishnan, Joseph P Hendrick, Eric J Nestler, Robert E Davis, Lawrence P Wennogle, Sharon Mates, Gretchen L Snyder, Kimberly E Vanover, Hongwen Zhu, Diane B Miller, James P O'Callaghan, John Tomesch, Peng Li, Qiang Zhang, Vaishnav Krishnan, Joseph P Hendrick, Eric J Nestler, Robert E Davis, Lawrence P Wennogle, Sharon Mates
Abstract
Rationale: Schizophrenia remains among the most prevalent neuropsychiatric disorders, and current treatment options are accompanied by unwanted side effects. New treatments that better address core features of the disease with minimal side effects are needed.
Objectives: As a new therapeutic approach, 1-(4-fluoro-phenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) is currently in human clinical trials for the treatment of schizophrenia. Here, we characterize the preclinical functional activity of ITI-007.
Results: ITI-007 is a potent 5-HT2A receptor ligand (K i = 0.5 nM) with strong affinity for dopamine (DA) D2 receptors (K i = 32 nM) and the serotonin transporter (SERT) (K i = 62 nM) but negligible binding to receptors (e.g., H1 histaminergic, 5-HT2C, and muscarinic) associated with cognitive and metabolic side effects of antipsychotic drugs. In vivo it is a 5-HT2A antagonist, blocking (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced headtwitch in mice with an inhibitory dose 50 (ID50) = 0.09 mg/kg, per oral (p.o.), and has dual properties at D2 receptors, acting as a postsynaptic D2 receptor antagonist to block D-amphetamine hydrochloride (D-AMPH) hyperlocomotion (ID50 = 0.95 mg/kg, p.o.), yet acting as a partial agonist at presynaptic striatal D2 receptors in assays measuring striatal DA neurotransmission. Further, in microdialysis studies, this compound significantly and preferentially enhances mesocortical DA release. At doses relevant for antipsychotic activity in rodents, ITI-007 has no demonstrable cataleptogenic activity. ITI-007 indirectly modulates glutamatergic neurotransmission by increasing phosphorylation of GluN2B-type N-methyl-D-aspartate (NMDA) receptors and preferentially increases phosphorylation of glycogen synthase kinase 3β (GSK-3β) in mesolimbic/mesocortical dopamine systems.
Conclusion: The combination of in vitro and in vivo activities of this compound support its development for the treatment of schizophrenia and other psychiatric and neurologic disorders.
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References
- Alimohamad H, Rajakumar N, Seah YH, Rushlow W. Antipsychotics alter the protein expression levels of beta-catenin and GSK-3 in the rat medial prefrontal cortex and striatum. Biol Psychiatry. 2005;57:533–42. doi: 10.1016/j.biopsych.2004.11.036.
- Ancoli-Israel S, Vanover KE, Weiner DM, Davis RE, van Kammen DP. Pimavanserin tartrate, a 5-HT(2A) receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers. Sleep Med. 2011;12:134–141. doi: 10.1016/j.sleep.2010.10.004.
- Auclair A, Drouin C, Cotecchia S, Glowinski J, Tassin J-P. 5-HT2A and α1b-adrenergic receptors entirely mediate dopamine release, locomotor response, and behavioral sensitization to opiates and psychostimulants. Eur J Neurosci. 2004;20:3073–3084. doi: 10.1111/j.1460-9568.2004.03805.x.
- Beaulieu J-M, Gainetdinov RR, Caron MG. Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol. 2009;49:327–347. doi: 10.1146/annurev.pharmtox.011008.145634.
- Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggeia DW, Nestler EJ. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006;311:864–8. doi: 10.1126/science.1120972.
- Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM. RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology. 1997;36:621–9. doi: 10.1016/S0028-3908(97)00049-X.
- Brennan JA, Graf R, Grauer SM, Navarra RL, Pulicicchio CM, Hughes ZA, Lin Q, Wantuch C, Rosenzweig-Lipson S, Pruthi F, Lai M, Smith D, Goutier W, van de Neut M, Robichaud AJ, Rotella D, Feenstra RW, Kruse C, Broqua P, Beyer CE, McCreary AC, Pausch MH, Marquis KL. WS-50030 [7-[4-[3-(3-(1H-inden-3-yl)propyl]piperazin-1-yl)-1,3-benzoxazol-2(3H)-one]: a novel dopamine D2 receptor partial agonist/serotonin uptake inhibitor with preclinical antipsychotic-like and antidepressant-like activity. J Pharmacol Exp Ther. 2010;332:190–210. doi: 10.1124/jpet.109.157388.
- Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca R, Molinoff PB. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther. 2002;302:381–9. doi: 10.1124/jpet.102.033175.
- Carty NC, Xu J, Kurup P, Brouillette J, Goebel-Goody SM, Austin DR, Yuan P, Chen G, Correa PR, Haroutunian V, Pittenger C, Lombroso PJ. The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications. Transl Psychiatr. 2012
- Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, Ferguson D, Tsai HC, Pomeranz L, Christoffel DJ, Nectow AR, Ekstrand M, Domingos A, Mazei-Robison MS, Mouzon E, Lobo MK, Neve RL, Friedman JM, Russo SJ, Deisseroth K, Nestler EJ, Han MH. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2013;493:532–536. doi: 10.1038/nature11713.
- Clark D, Hjorth S, Carlsson A. (+)- and (−)-3-PPP exhibit different intrinsic activity at striatal dopamine autoreceptors controlling dopamine synthesis. Eur J Pharmacol. 1984;106:185–9. doi: 10.1016/0014-2999(84)90694-0.
- Conn PJ, Sanders-Bush E. Selective 5-HT-2 antagonists inhibit serotonin stimulated phosphatidylinositol metabolism in cerebral cortex. Neuropharmacology. 1984;23:993–996. doi: 10.1016/0028-3908(84)90017-0.
- Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science. 1976;192:481–483. doi: 10.1126/science.3854.
- Davis K, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatr. 1991;148:1474–1486. doi: 10.1176/ajp.148.11.1474.
- Factor SA, Friedman JH. The emerging role of clozapine in the treatment of movement disorders. Mov Disord. 1997;12:483–496. doi: 10.1002/mds.870120403.
- Field JR, Walker AG, Conn PJ. Targeting glutamate synapses in schizophrenia. Trends Mol Med. 2012;17:689–698. doi: 10.1016/j.molmed.2011.08.004.
- Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, Sun JH, Link JR, Abbaszade I, Hollis JM, Largent BL, Hartig PR, Hollis GF, Meunier PC, Robichaud AJ, Robertson DW. Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol. 2000;57:75–81.
- Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW. ACP-103, a 5-hydroxytriptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models. J Pharmacol Exp Ther. 2007;322:862–870. doi: 10.1124/jpet.107.121715.
- Goebel-Goody SM, Davies KD, Alvestad Linger RM, Freund RK, Browning MD. Phospho-regulation of synaptic and extrasynaptic N-methyl-D-aspartate receptors in adult hippocampal slices. Neuroscience. 2009;158:1446–59. doi: 10.1016/j.neuroscience.2008.11.006.
- Gyertyán I, Kiss B, Sághy K, Laszy J, Szabó G, Szabados T, Gémesi L, Pásztor G, Zájer-Balázs KM, Csongor EA, Domány G, Tihanyi K, Szombathelyi Z. Cariprazine (RGH-188), a potent D3/D2 dopamine receptor agonist, binds to dopamine D2 receptors in vivo and shows antipsychotic-like and precognitive effects in rodents. Neurochem Int. 2011;59:925–35. doi: 10.1016/j.neuint.2011.07.002.
- Harada K, Wu J, Haycock JW, Goldstein M. regulation of L-DOPA biosynthesis by site-specific phosphorylation of tyrosine hydroxylase in At-20 cells expressing wild-type and serine 40-substituted enzyme. J Neurochem. 1996;64:629–635.
- Harvey ML, Swallows CL, Cooper MA. A double dissociation in the effects of 5-HT2A and 5-HT2C receptors on the acquisition and expression of conditioned defeat in Syrian hamsters. Behav Neurosci. 2012;126:530–537. doi: 10.1037/a0029047.
- Hattori K, Uchino S, Isosaka T, Maekawa M, Iyo M, Sato T, Kohsaka S, Yagi T, Yuasa S. Fyn is required for haloperidol-induced catalepsy in mice. J Biol Chem. 2006;281:7129–7139. doi: 10.1074/jbc.M511608200.
- Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O’Laughlin IA, Meltzer HY. 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem. 2001;76:1521–1531. doi: 10.1046/j.1471-4159.2001.00154.x.
- Ichikawa J, Li Z, Dai J, Meltzer HY. Atypical antipsychotic drugs, quetiapine, iloperidone, and melperone, preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5-HT1A receptor agonism. Brain Res. 2002;956:349–357. doi: 10.1016/S0006-8993(02)03570-9.
- Jardemark K, Marcus MM, Shahid M, Svensson TH. Effects of asenapine on prefrontal N-methyl-D-aspartate receptor-mediated transmission: Involvement of dopamine D1 receptors. Synapse. 2010;64:870–874. doi: 10.1002/syn.20803.
- Javitt DC. Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors and dopamine-glutamate interactions. Int Rev Neurobiol. 2007;78:69–108. doi: 10.1016/S0074-7742(06)78003-5.
- Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatr. 1988;45:789–796. doi: 10.1001/archpsyc.1988.01800330013001.
- Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, Ali MW. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatr. 2002;63:763–71. doi: 10.4088/JCP.v63n0903.
- Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA, CATIE Investigators; Neurocognitive Working Group Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiat. 2007;64:633–647. doi: 10.1001/archpsyc.64.6.633.
- Krishnan V, Nestler EJ. Animal models of depression: molecular perspectives. Curr Top Behav Neurosci. 2011;7:121–47. doi: 10.1007/7854_2010_108.
- Kroeze WK, Hufelsen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL. Hi-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology. 2003;28:519–26. doi: 10.1038/sj.npp.1300027.
- Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Jr, Charney DS. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatr. 1994;51:199–214. doi: 10.1001/archpsyc.1994.03950030035004.
- Laruelle M, Frankle G, Narendran R, Kegeles LS, Abi-Dargham A. Mechanism of action of antipsychotic drugs: from dopamine D2 receptor antagonism to glutamate NMDA facilitation. Clin Ther. 2005;2:S16–S24. doi: 10.1016/j.clinthera.2005.07.017.
- Li X, Rosborough KM, Friedman AB, Zhu W, Roth KA. Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics. Int J Neuropsychopharmacol. 2007;10:7–19. doi: 10.1017/S1461145706006547.
- Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–1223. doi: 10.1056/NEJMoa051688.
- Marek GJ, Martin-Ruiz R, Abo A, Artigas F. The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology. 2005;30:2205–2215. doi: 10.1038/sj.npp.1300762.
- Matsui-Sakata A, Ohtani H, Sawada Y. Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus. Drug Metab Pharmacokinet. 2005;20:368–378. doi: 10.2133/dmpk.20.368.
- Meltzer HY, Fatemi SH. The role of serotonin in schizophrenia and the mechanism of action of antipsychotic drugs. In: Kane JM, Moller HJ, Awouters F, editors. In Serotonin in antipsychotic treatment: mechanisms and clinical practice. New York: Marcel Dekker; 1996. pp. 77–107.
- Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther. 1989;251:238–46.
- Moghaddam B, Bunney BS. Acute effects of typical and atypical antipsychotic drugs on the release of dopamine from the prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study. J Neurochem. 1990;54:1755–1760. doi: 10.1111/j.1471-4159.1990.tb01230.x.
- Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacol Rev. 2012;37:4–15. doi: 10.1038/npp.2011.181.
- Morairty SR, Hedley L, Flores J, Martin R, Kilduff TS. Selective 5-HT2A and 5-HT6 receptor antagonists promote sleep in rats. Sleep. 2008;31:34–44.
- Nakai S, Hirose T, Uwahodo Y, Imaoka T, Okazaki H, Miwa T, Nakai M, Yamada S, Dunn B, Burris KD, Molinoff PB, Tottori K, Altar CA, Kikuchi T. Diminished catalepsy and dopamine metabolism distinguish aripiprazole from haloperidol or risperidone. Eur J Pharmacol. 2003;472:89–97. doi: 10.1016/S0014-2999(03)01857-0.
- Nakazawa T, Komai S, Tezuka T, Hisatsune C, Umemori H, Semba K, Mishina M, Manabe T, Yamamoto T. Characterization of fyn-mediated tyrosine phosphorylation sites on GluR epsilon 2 (NR2B) subunit of the N-methyl-D-aspartate receptor. J Biol Chem. 2001;276:693–699. doi: 10.1074/jbc.M008085200.
- Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiat. 2008;13:27–35. doi: 10.1038/sj.mp.4002066.
- Ohno Y, Ishida K, Ikeda K, Ishibashi T, Okada K, Nakamura M. Evaluation of bradykinesia induction by SM-9018, a novel 5-HT2 and D2 receptor antagonist, using the mouse pole test. Pharmacol Biochem Behav. 1994;49:19–23. doi: 10.1016/0091-3057(94)90451-0.
- Owens JM, Morgan WN, Plott SJ, Nemeroff CB. Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther. 1997;283:1305–22.
- Owens JM, Knight DL, Nemeroff CB. Second generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Encéphale. 2002;28:350–5.
- Pälvimäki EP, Roth BL, Majasuo H, Laakso A, Kuoppamäki M, Syvälahti E, Hietala J. Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor. Psychopharmacol (Berl) 1996;126:234–40. doi: 10.1007/BF02246453.
- Patel JK, Buckley PF, Woolson S, Hamer RM, McEvoy JP, Perkins DO, Lieberman JA, Investigators CAFÉ. Metabolic profiles of second-generation antipsychotics in early psychosis: findings from the CAFÉ study. Schizophr Res. 2009;111:9–16. doi: 10.1016/j.schres.2009.03.025.
- Popa D, Lena C, Fabre V, Prenat C, Gingrich J, Escourrou P, Hamon M, Adrien J. Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control and functional adaptations in knock-out mice lacking 5-HT2A receptors. J Neurosci. 2005;25:11231–11238. doi: 10.1523/JNEUROSCI.1724-05.2005.
- Porter RHP, Benwell KR, Lam H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ. Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B, and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol. 1999;128:13–20. doi: 10.1038/sj.bjp.0702751.
- Reynolds GP, Kirk SL. Metabolic side effects of antipsychotic drug treatment—pharmacological mechanisms. Pharmacol Ther. 2010;125:169–179. doi: 10.1016/j.pharmthera.2009.10.010.
- Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev. 2004;3:353–9.
- Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000;102:2836–41. doi: 10.1161/01.CIR.102.23.2836.
- Rygula R, Abumaria N, Havemann-Reinecke U, Rüther E, Hiemke C, Zernig G, Fuchs E, Flügge G. Pharmacological validation of a chronic social stress model of depression in rats: effects of reboxetine, haloperidol and diazepam. Behav Pharmacol. 2008;19:183–196. doi: 10.1097/FBP.0b013e3282fe8871.
- Sánchez C, Hyttel J. Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol. 1999;19:467–89. doi: 10.1023/A:1006986824213.
- Schwartz TL, Sachdeva S, Stahl SM. Glutamate neurocircuitry: theoretical underpinnings in schizophrenia. Front Pharmacol. 2012;3:195. doi: 10.3389/fphar.2012.00195.
- Stoof JC, Kebabian JW. Opposing roles for D-1 and D-2 dopamine receptors in the efflux of cyclic AMP from rat neostriatum. Nature. 1981;294:366–8. doi: 10.1038/294366a0.
- Sutherland C, Cohen P. The alpha-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p70 S6 kinase or MAP kinase-activated protein kinase-1 in vitro. FEBS Lett. 1994;338:37–42. doi: 10.1016/0014-5793(94)80112-6.
- Svensson K, Eriksson E, Carlsson A. Partial dopamine receptor agonists reverse behavioral, biochemical, and neuroendocrine effects of neuroleptics in the rat: potential treatment of extrapyramidal side effects. Neuropharmacology. 1993;32:1037–45. doi: 10.1016/0028-3908(93)90069-F.
- Tamminga CA, Buchanan RW, Gold JM. The role of negative symptoms and cognitive dysfunction in schizophrenia outcome. Int Clin Psychopharmacol. 1998;13(Suppl 3):S21–6. doi: 10.1097/00004850-199803003-00004.
- Vanover KE, Davis RE. Role of 5-HT2A antagonists in the treatment of insomnia. Nat Sci Sleep. 2010;2:139–150. doi: 10.2147/NSS.S6849.
- Wadenberg ML, Soliman A, VanderSpek SC, Kapur S. Dopamine D2 receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects. Neuropsychopharmacology. 2001;25:633–41. doi: 10.1016/S0893-133X(01)00261-5.
- Zhu H, O’Brien JJ, O’Callaghan JP, Miller DB, Zhang Q, Rana M, Tsui T, Peng Y, Tomesch J, Hendrick JP, Wennogle LP, Snyder GL. Nerve agent exposure elicits site-specific changes in protein phosphorylation in mouse brain. Brain Res. 2010;1342:11–23. doi: 10.1016/j.brainres.2010.04.034.
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