Schizophrenia Research
Volume 93, Issue 1 , Pages 42-50 , July 2007

A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia

  • Mark S. George

      Affiliations

    • Brain Stimulation Laboratory (BSL), Psychiatry Department, Medical University of South Carolina (MUSC) 29425, United States
    • Corresponding Author InformationCorresponding author. 67 President Street, Room 502 N IOP Charleston, SC, 29425, United States. Tel.: +1 843 876 5142; fax: +1 843 792 5702.
    • ,
  • Christine E. Molnar

      Affiliations

    • Brain Stimulation Laboratory (BSL), Psychiatry Department, Medical University of South Carolina (MUSC) 29425, United States
    • ,
  • Emily L. Grenesko

      Affiliations

    • Brain Stimulation Laboratory (BSL), Psychiatry Department, Medical University of South Carolina (MUSC) 29425, United States
    • ,
  • Berry Anderson

      Affiliations

    • Brain Stimulation Laboratory (BSL), Psychiatry Department, Medical University of South Carolina (MUSC) 29425, United States
    • ,
  • Qiwen Mu

      Affiliations

    • Brain Stimulation Laboratory (BSL), Psychiatry Department, Medical University of South Carolina (MUSC) 29425, United States
    • ,
  • Kevin Johnson

      Affiliations

    • Brain Stimulation Laboratory (BSL), Psychiatry Department, Medical University of South Carolina (MUSC) 29425, United States
    • ,
  • Ziad Nahas

      Affiliations

    • Brain Stimulation Laboratory (BSL), Psychiatry Department, Medical University of South Carolina (MUSC) 29425, United States
    • ,
  • Michael Knable

      Affiliations

    • Stanley Medical Research Institute, Bethesda MD 20814, United States
    • ,
  • Prabhavathi Fernandes

      Affiliations

    • Formerly of DarPharma Inc, Raleigh, NC, United States
    • ,
  • Jorge Juncos

      Affiliations

    • Department of Neurology, Emory University School of Medicine, Atlanta GA 30329, United States
    • ,
  • Xuemei Huang

      Affiliations

    • Departments of Neurology (XH, RBM), and Psychiatry, Pharmacology and Medicinal Chemistry (RBM), University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States
    • ,
  • David E. Nichols

      Affiliations

    • Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, W. Lafayette IN 47907, United States
    • ,
  • Richard B. Mailman

      Affiliations

    • Departments of Neurology (XH, RBM), and Psychiatry, Pharmacology and Medicinal Chemistry (RBM), University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States

Received 2 October 2006 ,Revised 28 February 2007 ,Accepted 5 March 2007.

References 

  1. Abi-Dargham A. Do we still believe in the dopamine hypothesis? New data bring new evidence. Int. J. Neuropsychopharmacol. 2004;7(Suppl 1):S1–S5
  2. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Br. J. Psychiatry. 1989;(7):49–58(Suppl. Nov.)
  3. Annett M. A classification of hand preference by association analysis. Br. J. Psychol. 1970;61:303–321
  4. Appelbaum PS, Grisso T. The MacArthur Competence Assessment Tool. Clin. Res. 1996;1:
  5. Arnsten AF, Li BM. Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol. Psychiatry. 2004;57:1377–1384
  6. Arnsten AF, Cai JX, Murphy BL, Goldman-Rakic PS. Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl). 1994;116:143–151
  7. Barch DM, Csernansky J, Conturo T, Snyder AZ, Ollinger J. Working and long-term memory deficits in schizophrenia. Is there a common underlying prefrontal mechanism?. J. Abnorm. Psychology. 2002;111:478–494
  8. Blanchet PJ, Fang J, Gillespie M, Sabounjian L, Locke KW, Gammans R, et al. Effects of the full dopamine D1 receptor agonist dihydrexidine in Parkinson's disease. Clin. Neuropharmacol. 1998;21:339–343
  9. Boyson SJ, Mcgonigle P, Molinoff PB. Quantitative autoradiographic localization of the D1 and D2 subtypes of dopamine receptors in rat brain. J. Neurosci. 1986;6:3177–3188
  10. Brewster WK, Nichols DE, Riggs RM, Mottola DM, Lovenberg TW, Lewis MH, et al. Trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine: a highly potent selective dopamine D1 full agonist. J. Med. Chem. 1990;33:1756–1764
  11. Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharm. Toxicol. (Copenh). 1963;20:140–144
  12. Castner SA, Williams GV, Goldman-Rakic PS. Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science. 2000;287:2020–2022
  13. Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science. 1976;192:481–483
  14. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am. J. Psychiatry. 1991;148:1474–1486
  15. De Beaurepaire R, Labelle A, Naber D, Jones BD, Barnes TR. An open trial of the D1 antagonist SCH 39166 in six cases of acute psychotic states. Psychopharmacology (Berl). 1995;121:323–327
  16. Den Boer JA, Van Megen HJ, Fleischhacker WW, Louwerens JW, Slaap BR, Westenberg HG, et al. Differential effects of the D1-DA receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia. Psychopharmacology (Berl). 1995;121:317–322
  17. Goldman-Rakic PS. The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biol. Psychiatry. 1999;46:650–661
  18. Goldman-Rakic PS, Lidow MS, Gallager DW. Overlap of dopaminergic, adrenergic, and serotoninergic receptors and complementarity of their subtypes in primate prefrontal cortex. J. Neurosci. 1990;10:2125–2138
  19. Goldman-Rakic PS, Castner SA, Svensson TH, Siever LJ, Williams GV. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive function. Psychopharmacology. 2004;174:3–16
  20. Gonzalez-Islas C, Hablitz JJ. Dopamine enhances EPSCs in layer II-III pyramidal neurons in rat prefrontal cortex. J. Neurosci. 2003;23:867–875
  21. Green M. What are the functional consequences of neurocognitive deficits in schizophrenia?. Am. J. Psychiatry. 1996;153:321–330
  22. Karlsson P, Smith L, Farde L, Harnryd C, Sedvall G, Wiesel FA. Lack of apparent antipsychotic effect of the D1-dopamine receptor antagonist SCH39166 in acutely ill schizophrenic patients. Psychopharmacology (Berl). 1995;121:309–316
  23. Lachowicz JE, Sibley DR. Molecular characteristics of mammalian dopamine receptors. Pharmacol. Toxicol. 1997;81:105–113
  24. Lidow MS, Goldman-Rakic PS. A common action of clozapine, haloperidol, and remoxipride on D1- and D2-dopaminergic receptors in the primate cerebral cortex. Proc. Natl. Acad. Sci. U. S. A. 1994;91:4353–4356
  25. Lidow MS, Elsworth JD, Goldman-Rakic PS. Down-regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs. J. Pharmacol. Exp. Ther. 1997;281:597–603
  26. Lovenberg TW, Brewster WK, Mottola DM, Lee RC, Riggs RM, Nichols DE, et al. Dihydrexidine, a novel selective high potency full dopamine D-1 receptor agonist. Eur. J. Pharmacol. 1989;166:111–113
  27. Mailman RB, Schulz DW, Lewis MH, Staples L, Rollema H, Dehaven DL. SCH-23390: a selective D1 dopamine antagonist with potent D2 behavioral actions. Eur. J. Pharmacol. 1984;101:159–160
  28. Mailman RB, Huang X, Nichols DE. Dopamine D1 full agonists and Parkinson's disease. Curr. Opin. Investig. Drugs. 2001;21582–21591
  29. Michaelides MR, Hong Y, Didomenico SJ, Asin KE, Britton DR, Lin CW, et al. (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]-phenanthrene-9,10-diol (A-86929): a potent and selective dopamine D1 agonist that maintains behavioral efficacy following repeated administration and characterization of its diacetyl prodrug (ABT-431). J. Med. Chem. 1995;38:3445–3447
  30. Mottola DM, Brewster WK, Cook LL, Nichols DE, Mailman RB. Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist. J. Pharmacol. Exp. Ther. 1992;262:383–393
  31. Mu, Q., Johnson, K., Morgan, P., Grenesko, E., Molnar, C., Anderson, B., Nahas, Z., Kozel, F.A., Kose, S., Knable, M., Fernandes, P., Nichols, D., Mailman, R., George, M.S., in press. A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal cortical perfusion in schizophrenia. Schizophr. Res.
  32. Pennebaker JW. The Psychology of Physical Symptoms. New York: Springer-Verlag; 1982;
  33. Rascol O, Blin O, Thalamas C, Descombes S, Soubrouillard C, Azulay P, et al. ABT-431, a D1 receptor agonist prodrug, has efficacy in Parkinson's disease. Ann. Neurol. 1999;45:736–741
  34. Salmi P, Isacson R, Kull B. Dihydrexidine-the first full dopamine D1 receptor agonist. CNS Drug Rev. 2004;10:230–242
  35. Sawaguchi T, Goldman-Rakic PS. D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science. 1991;251:947–950
  36. Schneider JS, Sun ZQ, Roeltgen DP. Effects of dopamine agonists on delayed response performance in chronic low-dose MPTP-treated monkeys. Pharmacol. Biochem. Behav. 1994;48:235–240
  37. Schulz DW, Stanford EJ, Wyrick SW, Mailman RB. Binding of [3H]SCH23390 in rat brain: regional distribution and effects of assay conditions and GTP suggest interactions at a D1-like dopamine receptor. J. Neurochem. 1985;45:1601–1611
  38. Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science. 1975;188:1217–1219
  39. Steele TD, Hodges DB, Levesque TR, Locke KW, Sandage BW. The D1 agonist dihydrexidine releases acetylcholine and improves cognition in rats. Ann. N. Y. Acad. Sci. 1996;777:427–430
  40. Taylor JR, Lawrence MS, Redmond DEJ, Elsworth JD, Roth RH, Nichols DE, et al. Dihydrexidine, a full dopamine D1 agonist, reduces MPTP-induced parkinsonism in monkeys. Eur. J. Pharmacol. 1991;199:389–391
  41. Watson D, Weber K, Assenheimer JS, Clark LA, Strauss ME, Mccormick RA. Testing a tripartite model: I. Evaluating the convergent and discriminant validity of anxiety and depression symptom scales. J. Abnorm. Psychology. 1995;104:3–14

PII: S0920-9964(07)00119-3

doi: 10.1016/j.schres.2007.03.011

Schizophrenia Research
Volume 93, Issue 1 , Pages 42-50 , July 2007

Article Tools

* Image Usage & Resolution