Developing small molecule nonpeptidergic drugs for the treatment of anxiety disorders: Is the challenge still ahead?

Current Topics in Behavioral Neurosciences

Volumn 2, Issue , 2010, Pages 415-428

  Steckler, Thomas ^a  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

Author keywords

ANP; Atrial natriuretic peptide; CCK2 Antagonist; Cholecystokinin; Clinical trial; Corticotropin releasing factor; CRF1 antagonist; Neurokinin; NK1 Antagonist; NK3 Antagonist; Oxytocin; Proof of concept; Substance P

Indexed keywords

3 (6 DIMETHYLAMINO 4 METHYL 3 PYRIDINYL) 7 DIPROPYLAMINO 2,5 DIMETHYLPYRAZOLO[1,5 A]PYRIMIDINE; ANTALARMIN; APREPITANT; ATRIAL NATRIURETIC FACTOR; BUSPIRONE; CHOLECYSTOKININ B RECEPTOR ANTAGONIST; CITALOPRAM; CORTICOTROPIN RELEASING FACTOR ANTAGONIST; CP 316 311; DIAZEPAM; LY 759274; NEUROKININ 1 RECEPTOR ANTAGONIST; NEUROKININ 3 RECEPTOR ANTAGONIST; NEUROPEPTIDE; OSANETANT; OXYTOCIN; PAROXETINE; PENTAGASTRIN; PLACEBO; UNCLASSIFIED DRUG; VOFOPITANT; ACENAPHTHENE DERIVATIVE; ANXIOLYTIC AGENT; CHOLECYSTOKININ B RECEPTOR; CORTICOTROPIN RELEASING FACTOR RECEPTOR; CRF RECEPTOR TYPE 1; MORPHOLINE DERIVATIVE; NBI 34041; NBI-34041; NEUROKININ 1 RECEPTOR; NEUROKININ 3 RECEPTOR;

AMINOTRANSFERASE BLOOD LEVEL; ANXIETY DISORDER; ARTICLE; DEPRESSION; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENCY; DRUG SYNTHESIS; DRUG TARGETING; DRUG TREATMENT FAILURE; GENERALIZED ANXIETY DISORDER; HAMILTON ANXIETY SCALE; HISTORY OF MEDICINE; HUMAN; LIVER TOXICITY; NEPHROTOXICITY; NONHUMAN; OBSESSIVE COMPULSIVE DISORDER; PANIC; PEPTIDE ANALYSIS; PRIORITY JOURNAL; SIDE EFFECT; SOCIAL PHOBIA; ANIMAL; CHEMISTRY; CLINICAL TRIAL (TOPIC); DRUG ANTAGONISM; DRUG DEVELOPMENT; REVIEW; TREATMENT OUTCOME;

ACENAPHTHENES; ANIMALS; ANTI-ANXIETY AGENTS; ANXIETY DISORDERS; ATRIAL NATRIURETIC FACTOR; CLINICAL TRIALS AS TOPIC; DRUG DISCOVERY; HUMANS; MORPHOLINES; OXYTOCIN; RECEPTOR, CHOLECYSTOKININ B; RECEPTORS, CORTICOTROPIN-RELEASING HORMONE; RECEPTORS, NEUROKININ-1; RECEPTORS, NEUROKININ-3; TREATMENT OUTCOME;

EID: 79952261762     PISSN: 18663370     EISSN: 18663389     Source Type: Book Series    
DOI: 10.1007/7854_2009_14     Document Type: Article

References (77)

1. Adams JB, Pyke RE, Costa J, Cutler NR, Schweizer E, Wilcox CS, Wisselink PG, Greiner M, Pierce MW, Pande AC (1995) A doubleblind, placebo-controlled study of a CCK-B receptor antagonist, CI-988, in patients with generalized anxiety disorder. J Clin Psychopharmacol 15:428-434
2. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Fujimiya M, Katsuura G, Makino S, Fujino MA, Kasuga M(2001) A role of ghrelin in neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology 74:143-147
3. Bakshi VP, Smith-Roe S, Newman SM, Grigoriadis DE, Kalin NH (2002) Reduction of stressinduced behaviour by antagonism of corticotropin-releasing factor 2 (CRF2) receptors in lateral septum or CRF1 receptors in amygdala. J Neurosci 22:2926-2935
4. Balon R, Ramesh C (1996) Calcium channel blockers for anxiety disorders? Annals Clin. Psychiatry 8:215-220
5. Behan DP, Heinrichs SC, Troncoso JC, Liu XJ, Kawas CH, Ling N, De Souza EB (1995) Displacement of corticotropin releasing factor from its binding protein as a possible treatment for Alzheimer's disease. Nature 378:284-287
6. Binneman B, Feltner D, Kolluri S, Shi Y, Qiu R, Stiger T (2008) A 6-week randomized, placebocontrolled trial of CP-316, 311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry 165:617-620
7. Biro E, Sarnyai Z, Penke B, Szabo G, Telegdy G (1993) Role of endogenous corticotropinreleasing factor in mediation of neuroendocrine and behavioural responses to cholecystokinin octapeptide sulfate ester in rats. Neuroendocrinology 57:340-345
8. Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL (2002) Sniffing neuropeptides: a transnasal approach to the human brain. Nature Neurosci 5:514-516
9. Bradwejn J, Koszycki D, Couetoux du Tertre A, Van Megen H, Den Boer J, Westenberg H (1994) The panicogenic effects of cholecystokinintetrapeptide are antagonized by L-365, 260, a central cholecystokinin receptor antagonist, in patients with panic disorder. Arch Gen Psychiatry 51:486-493
10. Bradwejn J, Koszycki D, Paradis M, Reece P, Hinton J, Sedman A (1995) Effect of CI-988 on cholecystokinin tetrapeptide-induced panic symptoms in healthy volunteers. Biol Psychiatry 38:742-746
11. Brawman-Mintzer O, Lydiard RB, Bradwejn J, Villarreal G, Knapp R, Emmanuel N, Ware MR, He Q, Ballenger JC (1997) Effects of the cholecystokinin agonist pentagastrin in patients with generalized anxiety disorder. Am J Psychiatry 154:700-702
12. Cano V, Caicoya E, Ruiz-Gayo M(2003) Effect of peripheral cholecystokinin receptor agonists on c-Fos expression in brain sites mediating food consumption in rats. Neurosci Lett 343:13-16
13. Canteras NS, Resstel LB, Bertoglio LJ, de Padua Carobrez A, Guimaraes FS (2009) Neuroanatomy of anxiety. In: Steckler T, Stein M (eds) Behavioral neurobiology of anxiety and its treatment. Curr Top Behav Neurol Springer, Heidelberg
14. Carlini VP, Monzon ME, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, De Barioglio SR (2002) Ghrelin increases anxiety-like behavior and memory retention in rats. Biochem Biophys Res Commun 299:739-743
15. Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, De Barioglio SR (2004) Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Commun 313:635-641
16. Comer SD, Hoenicke EM, Sable AI, McNutt RW, Chang KJ, Mosberg HI, Woods JH (1993) Convulsive effects of systemic administration of delta opioid agonist BW373U86 in mice. J Pharmacol Exp Ther 267:888-895
17. Cowley DS, Adams JB, Pyke RE, Cook J, Zaccharias P, Wingerson D, Roy-Byrne PP (1996) Effect of CI-988, a cholecystokinin-B receptor antagonist, on lactate-induced panic. Biol Psychiatry 40:550-552
18. Crawley JN, Corwin RL (1994) Biological actions of cholecystokinin. Peptides 15:731-755
19. Domes G, Heinrichs M, Glascher J, Buchel C, Braus DF, Herpertz SC (2007) Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry 62:1187-1190
20. Dornonville de la Cour C, Bjorkqvist M, Sandvik AK, Bakke I, Zhao CM, Chen D, Hakanson R (2001) A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control. Regul Pept 99:141-150
21. Ebner K, Rupniak NM, Saria A, Singewald N (2004) Substance P in the medial amygdala: emotional stress-sensitive release and modulation of anxiety-related behavior in rats. Proc Natl Acad Sci USA 101:4280-4285
22. Fossey MD, Lydiard RB, Ballenger JC, Laraia MT, Bissette G, Nemeroff CB (1996) Cerebrospinal fluid corticotropin-releasing factor concentrations in patients with anxiety disorders and normal comparison subjects. Biol Psychiatry 39:703-707
23. Furmark T, Appel L, Michelgard A, Wahlstedt K, Ahs F, Zancan S, Jacobsson E, Flyckt K, Grohp M, Bergstrom M, Pich EM, Nilsson LG, Bani M, Langstrom B, Fredrikson M (2005) Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo. Biol Psychiatry 58:132-142
24. Goddard AW, Woods SW, Money R, Pande AC, Charney DS, Goodman WK, Heninger GR, Price LH (1999) Effects of the CCK(B) antagonist CI-988 on responses to mCPP in generalized anxiety disorder. Psychiatry Res 85:225-240
25. Gold PW, Pigott TA, Kling MA, Kalogeras K, Chrousos GP (1988) Basic and clinical studies with corticotropin-releasing hormone. Implications for a possible role in panic disorder. Psychiatric Clin North Am 11:327-334
26. Hargreaves R (2002) Imaging substance P receptors (NK1) in the living human brain using positron emission tomography. J Clin Psychiatry 63(Suppl 11):18-24
27. Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U (2003) Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 54:1389-1398
28. Hokfelt T, Bartfai T, Bloom F (2003) Neuropeptides: opportunities for drug discovery. Lancet Neurol 2:463-472
29. Holmes A, Heilig M, Rupniak NMJ, Steckler T, Griebel G (2003) Neuropeptide systems as therapeutic targets for depression and anxiety disorders. Trends Pharmacol Sci 24:580-588
30. Holsboer F, von Bardeleben U, Buller R, Heuser I, Steiger A (1987) Stimulation response to corticotropin-releasing hormone (CRH) in patients with depression, alcoholism and panic disorder. Horm Metabol Res Suppl 16:80-88
31. Holst B, Cygankiewicz A, Halkjar JT, Ankersen M, Schwartz TW (2003) High constitutive signaling of the ghrelin receptor-identification of a potent inverse agonist. Mol Endocrinol 17:2201-2210
32. Holst B, Brandt E, Bach A, Heding A, Schwartz TW (2005) Nonpeptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist and as positive or negative allosteric modulators of ghrelin signaling. Mol Endocrinol 19:2400-2411
33. Holst B, Lang M, Brandt E, Bach A, Howard A, Frimurer TM, Beck-Sickinger A, Schwartz TW (2006) Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. Mol Pharmacol 70:936-946
34. Horn TL, Harder JB, Johnson WD, Curry PT, Parchment RE, Morrissey RL, Mellick PW, Calis KA, Gold PW, Rice KC, Contoreggi C, Charney DS, Cizza G, Glaze ER, Tomaszewski JE, McCormick DL (2008) Integration of in vivo and in vitro approaches to characterize the toxicity of Antalarmin, a corticotropin-releasing hormone receptor antagonist. Toxicology 248:8-17
35. Ising M, Zimmermann US, Kunzel HE, Uhr M, Foster AC, Learned-Coughlin SM, Holsboer F, Grigoriadis DE (2007) High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response. Neuropsychopharmacology 32:1941-1949
36. Kanehisa M, Akiyoshi J, Kitaichi T, Matsushita H, Tanaka E, Kodama K, Hanada H, Isogawa K (2006) Administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 30:1403-1407
37. Kask A, Rago L, Wikberg JE, Schioth HB(1998) Evidence for involvement of the melanocortinMC4 receptor in the effects of leptin on food intake and body weight. Eur J Pharmacol 360:15-19
38. Keller M, Montgomery S, Ball W, Morrison M, Snavely D, Liu G, Hargreaves R, Hietala J, Lines C, Beebe K, Reines S (2006) Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry 59:216-223
39. Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, Gruppe H, Mattay VS, Gallhofer B, Meyer-Lindenberg A (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25:11489-11493
40. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growthhormone-releasing acylated peptide from stomach. Nature 402:656-660
41. Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E (2005) Oxytocin increases trust in humans. Nature 435:673-676
42. Kramer MS, Cutler NR, Ballenger JC, Patterson WM, Mendels J, Chenault A, Shrivastava R, Matzura-Wolfe D, Lines C, Reines S (1995) A placebo-controlled trial of L-365, 260, a CCKB antagonist, in panic disorder. Biol Psychiatry 37:462-466
43. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlson EJ, Hargreaves RJ, Rupniak NM (1998) Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281:1640-1645
44. Kramer MS, Winokur A, Kelsey J, Preskorn SH, Rothschild AJ, Snavely D, Ghosh K, Ball WA, Reines SA, Munjack D, Apter JT, Cunningham L, Kling M, Bari M, Getson A, Lee Y (2004) Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology 29:385-392
45. Kronenberg G, Berger P, Tauber RF, Bandelow B, Henkel V, Heuser I (2005) Randomized, double-blind study of SR142801 (Osanetant). A novel neurokinin-3 (NK3) receptor antagonist in panic disorder with pre-and posttreatment cholecystokinin tetrapeptide (CCK-4) challenges. Pharmacopsychiatry 38:25-29
46. Landgraf R (1985) Plasma oxytocin concentrations in man after different routes of administration of synthetic oxytocin. Exp Clin Endocrinol 85:245-248
47. Landgraf R (2005) Neuropeptides in anxiety modulation. Handb Exp Pharmacol 169:335-369
48. Lines C, Challenor J, Traub M (1995) Cholecystokinin and anxiety in normal volunteers: an investigation of the anxiogenic properties of pentagastrin and reversal by the cholecystokinin receptor subtype B antagonist L-365, 260. Br J Clin Pharmacol 39:235-242
49. 2+channel blocker diltiazem and its metabolites as ghrelin receptor agonists. Mol Pharmacol 72:380-386
50. Makrigiannakis A, Zoumakis E, Kalantaridou S, Chrousos G, Gravanis A (2004) Participation of maternal and fetal CRH in early phases of human implantation: the role of antalarmin. Curr Drug Targets Immune Endocr Metabol Disord 4:75-78
51. McCann UD, Slate SO, Geraci M, Roscow-Terrill D, Uhde TW (1997) A comparison of the effects of intravenous pentagastrin on patients with social phobia, panic disorder and healthy controls. Neuropsychopharmacology 16:229-237
52. Mezey E, Reisine TD, Skirboll L, Beinfeld M, Kiss JZ (1985) Cholecystokinin in the medial parvocellular subdivision of the paraventricular nucleus. Co-existence with corticotropinreleasing hormone. Ann N Y Acad Sci 448:152-156
53. Michelgard A, Appel L, Pissiota A, Frans O, Langstrom B, Bergstrom M, Fredrikson M (2007) Symptom provocation in specific phobia affects the substance P neurokinin-1 receptor system. Biol Psychiatry 61:1002-1006
54. Nemeroff CB, Bremner JD, Foa EB, Mayberg HS, North CS, Stein MB (2006) Posttraumatic stress disorder: a state-of-the-science review. J Psychiatric Res 40:1-21
55. Pande AC, Greiner M, Adams JB, Lydiard RB, Pierce MW (1999) Placebo-controlled trial of the CCK-B antagonist, CI-988, in panic disorder. Biol Psychiatry 46:860-862
56. Rinaman L, Hoffman GE, Dohanics J, Le WW, Stricker EM, Verbalis JG (1995) Cholecystokinin activates catecholaminergic neurons in the caudal medulla that innervate the paraventricular nucleus of the hypothalamus in rats. J Comp Neurol 360:246-256
57. Rupniak NM, Webb JK, Fisher A, Smith D, Boyce S (2003) The substance P (NK1) receptor antagonist L-760735 inhibits fear conditioning in gerbils. Neuropharmacology 44:516-523
58. Sahuque LL, Kullberg EF, Mcgeehan AJ, Kinder JR, Hicks MP, Blanton MG, Janak PH, Olive MF (2006) Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes. Psychopharmacology 186:122-132
59. Sanchez-Fernandez C, Gonzalez C, Mercer LD, Beart PM, Ruiz-Gayo M, Fernandez-Alfonso MS (2003) Cholecystokinin induces cerebral vasodilatation via presynaptic CCK2 receptors: new implications for the pathophysiology of panic. J Cereb Blood Flow Metabol 23:364-370
60. Skuladottir GV, Jonsson L, Skarphedinsson JO, Mutulis F, Muceniece R, Raine A, Mutule I, Helgason J, Prusis P, Wikberg JE, Schioth HB (1999) Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist. Br J Pharmacol 126:27-34
61. Smoller JW, Rosenbaum JF, Biederman J, Kennedy J, Dai D, Racette SR, Laird NM, Kagan J, Snidman N, Hirshfeld-Becker D, Tsuang MT, Sklar PB, Slaugenhaupt SA (2003) Association of a genetic marker at the corticotropin-releasing hormone locus with behavioral inhibition. Biol Psychiatry 54:1376-1381
62. Smoller JW, Yamaki LH, Fagerness JA, Biederman J, Racette S, Laird NM, Kagan J, Snidman N, Faraone SV, Hirshfeld-Becker D, Tsuang MT, Slaugenhaupt SA, Rosenbaum JF, Sklar PB (2005) The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder. Biol Psychiatry 57:1485-1492
63. Sramek JJ, Kramer MS, Reines SA, Cutler NR (1994-1995) Pilot study of a CCKB antagonist in patients with panic disorder: preliminary findings. Anxiety 1:141-143
64. Steckler T (2005) CRF antagonists as novel treatment strategies for stress-related disorders. In: Steckler T, Kalin NH, Reul JMHM (eds) Handbook of stress and the brain, part 2: integrative and clinical aspects. Elsevier, Amsterdam, pp 373-407
65. Steckler T (2008) Peptide receptor ligands to treat anxiety disorders. In: Blanchard RJ, Blanchard DC, Griebel G, Nutt D (eds) Handbook of anxiety and fear. Elsevier, Amsterdam, pp 157-221
66. Steckler T, Dautzenberg F (2006) Corticotropin-releasing factor antagonists in affective disorders and drug dependence-an update. CNS Neurol Disorders Drug Targets 5:147-165
67. Steckler T, Holsboer F (1999) Corticotropin-releasing hormone receptor subtypes and emotion. Biol Psychiatry 46:1480-1508
68. Steckler T, Stein MB, Holmes A (2008) Developing novel anxiolytics: improving preclinical detection and clinical assessment. In: McArthur R, Borsini F (eds) Animal and translational models for CNS discovery, vol 1. Elsevier, Amsterdam, pp 117-132
69. Strohle A, Kellner M, Holsboer F, Wiedemann K (2001) Anxiolytic activity of atrial natriuretic peptide in patients with panic disorder. Am J Psychiatry 158:1514-1516
70. Tschop M, Smiley DL, Heiman ML (2000) Ghrelin induces adiposity in rodents. Nature 407:908-991
71. Van Megen HJ, Westenberg HG, Den Boer JA, Slaap B, Van Es-Radhakishun F, Pande AC (1997) The cholecystokinin-B receptor antagonist CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients. Psychopharmacology 129:243-248
72. Van Vliet IM, Westenberg HG, Slaap BR, Den Boer JA, Ho Pian KL (1997) Anxiogenic effects of pentagastrin in patients with social phobia and healthy controls. Biol Psychiatry 42:76-78
73. Wiedemann K, Jahn H, Yassouridis A, Kellner M(2001) Anxiolyticlike effects of atrial natriuretic peptide on cholecystokinin tetrapeptide-induced panic attacks: preliminary findings. Arch Gen Psychiatry 58:371-377
74. Yajima Y, Narita M, Takahashi-Nakano Y, Misawa M, Nagase H, Mizoguchi H, Tseng LF, Suzuki T (2000) Effects of differential modulation of mu-, delta-and kappa-opioid systems on bicuculline-induced convulsions in the mouse. Brain Res 862:120-126
75. Yehuda R, Giller EL, Southwick SM, Lowry MT, Mason JW (1991) Hypothalamic-pituitaryadrenal dysfunction in posttraumatic stress disorder. Biol Psychiatry 30:1031-1048
76. Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M, Holsboer F (2000) Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatric Res 34:171-181
77. Zorrilla EP, Koob GF (2004) The therapeutic potential of CRF1 antagonists for anxiety. Exp Opin Invest Drugs 13:799-828