Download PDF
Arzneimittelforschung 2010; 60(9): 544-552
DOI: 10.1055/s-0031-1296323
Antiemetics · Gastrointestinal Drugs · Urologic Drugs
Editio Cantor Verlag Aulendorf (Germany)

Arylalkylamine-, β-carboline-, quinolizine- and azecine-derived compounds and their in vitro interaction with the ionotropic 5-HT3 receptor: search for new lead structures

Christoph Enzensperger
1   Institut für Pharmazie, Lehrstuhl für Pharmazeutische/Medizinische Chemie, Friedrich Schiller Universität, Jena, Germany
3   Temporarily at Unilever Centre for Molecular Science Informatics, Department of Chemistry, Lensfield Road, Cambridge, UK
,
Jochen Lehmann
1   Institut für Pharmazie, Lehrstuhl für Pharmazeutische/Medizinische Chemie, Friedrich Schiller Universität, Jena, Germany
,
Katrin von Schroetter
2   Institut für Pharmazeutische/Medizinische Chemie, Abteilung Pharmakologie, Westfälische Wilhelms-Universität Münster, Münster, Germany
,
Anja Riyazi
2   Institut für Pharmazeutische/Medizinische Chemie, Abteilung Pharmakologie, Westfälische Wilhelms-Universität Münster, Münster, Germany
,
Eugen J. Verspohl
2   Institut für Pharmazeutische/Medizinische Chemie, Abteilung Pharmakologie, Westfälische Wilhelms-Universität Münster, Münster, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 December 2011 (online)

    Permissions and Reprints

Abstract

Specific Serotonin receptor agonists and antagonists are marketed with respect to various diseases, most prominently severe emesis. To identify new chemical classes with affinity for the serotonin 5-HT3 channel, several compounds were synthesized which can be structurally classified as arylalkylamines, azecines, quinolizines and β-carbolines. These were tested in three models: 1. direct effect on ileum (overall model for contracting or relaxant effect), 2. antiserotoninergic effects on rat ileum (crude serotonin model), 3. inhibitory effect on the 5-HT3 receptor channel complex expressed in N1E-115 cells (serotonin-induced [14C]guanidinium influx (specific model)). Key findings and conclusion: Several azecine-type compounds exhibit 5-HT3 receptor channel antagonistic properties at concentrations close to that of tropisetron (used as a positive control) and might serve as potential lead structures for the development of further 5-HT3 channel receptor antagonists.

Key words

Azecine - β-Carboline - 5-HT3 receptor - Phenylalkylamine - Quinolizine
 

  • References

  • 1 Cash BD, Chey WD. Review article: The role of serotonergic agents in the treatment of patients with primary chronic constipation. Aliment Pharmacol Ther. 2005; 22: 1047-60
    CrossrefPubMedGoogle Scholar
  • 2 Mössner R, Lesch KP. Role of serotonin in the immune system and in neuroimmune interactions. Brain Behav Immun. 1998; 12: 249-71
    CrossrefPubMedGoogle Scholar
  • 3 Surgand JS, Rodrigo J, Rognan D. A chemogenomic analysis of the transmembrane binding cavity of human G-pro-tein-coupled receptors. Proteins. 2006; 62: 509-38
    PubMedGoogle Scholar
  • 4 Costall B, Domeney AM, Gerrard PA, Kelly ME, Naylor RJ. Zacopride: anxiolytic profile in rodent and primate models of anxiety. J Pharm Pharmacol. 1988; 40: 302-5
    CrossrefPubMedGoogle Scholar
  • 5 Smith WT, Londborg PD, Blomgren SL, Tollefson CD, Sayler ME. Pilot study of zatosetron (LY277359) maleate, a 5-hydroxytryptamine-3 antagonist, in the treatment of anxiety. J Clin Psychopharmacol. 1999; 19: 125-31
    CrossrefPubMedGoogle Scholar
  • 6 Young R, Johnson DN. Anxiolytic-like activity of R(+)- and S(-)-zacopride in mice. Eur J Pharmacol. 1991; 201: 151-55
    CrossrefPubMedGoogle Scholar
  • 7 Lodge NJ, Li YW. Ion channels as potential targets for the treatment of depression. Curr Opin Drug Discov Devel. 2008; 11: 633-41
    PubMedGoogle Scholar
  • 8 Buhot MC, Mallert G. Segul. Serotonin receptors and cognitive behaviour-an update. IDrugs. 1999; 2: 426-37
    PubMedGoogle Scholar
  • 9 Sirota P, Mosheva T, Shabtay H, Giladi N, Korczyn AD. Use of the selective serotonin 3 receptor antagonist ondansetron in the treatment of neuroleptic-induced tardive dyskinesia. Am J Psychiatry. 2000; 157: 287-9
    CrossrefPubMedGoogle Scholar
  • 10 Zhang ZJ, Kang WH, Li Q, Wang XY, Yao SM, Ma AQ. Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: a double-blind, randomized, placebo-controlled study. Schizophr Res. 2006; 88: 102-10
    CrossrefPubMedGoogle Scholar
  • 11 Sellers EM, Toneatto T, Romach MK, Somer GR, Sobell LC, Sobell MB. Clinical efficacy of the 5-HT3 antagonist ondansetron in alcohol abuse and dependence. Alcohol Clin Exp Res. 1994; 18: 879-85
    CrossrefPubMedGoogle Scholar
  • 12 McKinzie DL, McBride WJ, Murphy JM, Lumeng L, Li TK. Effects of MDL 72222, a serotonin3 antagonist, on operant responding for ethanol by alcohol-preferring P rats. Alcohol Clin Exp Res. 2000; 24: 1500-4
    CrossrefPubMedGoogle Scholar
  • 13 Kankaanpaa A, Meririnne E, Seppala T. 5-HT3 receptor antagonist MDL 72222 attenuates cocaine- and mazindol-, but not methylphenidate-induced neurochemical and behavioral effects in the rat. Psychopharmacology (Berl). 2002; 159: 341-50
    CrossrefPubMedGoogle Scholar
  • 14 Kos T, Popik P, Pietraszek M, Schafer D, Danysz W, Dravolina O et al Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice. Eur Neuropsychopharmacol. 2006; 16: 297-10
    CrossrefPubMedGoogle Scholar
  • 15 Yoo JH, Nam YS, Lee SY, Jang CG. Dopamine neurotransmission is involved in the attenuating effects of 5-HT3 receptor antagonist MDL 72222 on acute methampheta-mine-induced locomotor hyperactivity in mice. Synapse. 2008; 62: 8-13
    CrossrefPubMedGoogle Scholar
  • 16 Fontana DJ, Daniels SE, Eglen RM, Wong EH. Stereoselective effects of (R)- and (S)-zacopride on cognitive performance in a spatial navigation task in rats. Neuropharmacology. 1996; 35: 321-327
    CrossrefPubMedGoogle Scholar
  • 17 Fontana DJ, Daniels SE, Henderson C, Eglen RM, Wong EH. Ondansetron improves cognitive performance in the Morris water maze spatial navigation task. Psychopharmacology (Berl). 1995; 120: 409-17
    CrossrefPubMedGoogle Scholar
  • 18 Bönisch H, Barann M, Graupner J, Göthert M. Characterization of 5-HT3 receptors of N1E-115 neuroblastoma cells by use of the influx of the organic cation [14C]-guanidi-nium. Br J Pharmacol. 1993; 108: 436-42
    CrossrefPubMedGoogle Scholar
  • 19 Abdel-Aziz H, Nahrstedt A, Petereit F, Windeck T, Ploch M, Verspohl EJ. 5-HT3 receptor blocking activity of arylal-kanes isolated from the rhizome of Zingiber officinale. Planta Med. 2005; 71: 609-16
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Glennon RA, Raghupathi R, Bartyzel P, Teitler M, Leonhardt S. Binding of phenylalkylamine derivatives at 5-HT1C and 5-HT2 serotonin receptors: evidence for a lack of selectivity. J Med Chem. 1992; 35: 734-40
    CrossrefPubMedGoogle Scholar
  • 21 Glennon RA, Gessner PK. Serotonin receptor binding affinities of tryptamine analogues. J Med Chem. 1979; 22: 428-32
    CrossrefPubMedGoogle Scholar
  • 22 Ho BT, Li KC, Walker KE, Tansey LW, Kralik PM, Mclsaac WM. Inhibitors of monoamine oxidase. VI. Effects of substitution on inhibitory activity of 6 (or 8)-substituted beta-carbolines. J Pharm Sc. 1970; 59: 1445-8
    CrossrefPubMedGoogle Scholar
  • 23 Schott Y, Decker M, Rommelspacher H, Lehmann J. 6-Hy-droxy- and 6-methoxy-beta-carbolines as acetyl- and bu-tyrylcholinesterase inhibitors. Bioorg Med Chem Lett. 2006; 16: 5840-3
    Google Scholar
  • 24 Fourneau JP, Delestrange Y. Dérives de la N-phényléthylè-nediamine. Bull Soc Chim France. 1947; 14: 827-38 French
    PubMedGoogle Scholar
  • 25 Schmutz J, Kunzle F. Piperazino-l’,2–l,2-Benzimidazole. Helv Chim Acta. 1956; 39: 1144-56
    CrossrefPubMedGoogle Scholar
  • 26 HoefgenBDecker M, Mohr P, Schramm AM, Rostom SA, ElSubbagh H et al Dopamine/serotonin receptor ligands. 10: SAR studies on azecine-type dopamine receptor ligands by functional screening at human cloned Dl, D2L, and D5 receptors with a microplate reader based calcium assay lead to a novel potent D1/D5 selective antagonist. J Med Chem. 2006; 49: 760-9
    CrossrefPubMedGoogle Scholar
  • 27 Mohr P, Decker M, Enzensperger C, Lehmann J. Dopamine/serotonin receptor ligands. 12(1): SAR studies on hexahydro-dibenz[d,g]azecines lead to 4-chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecin-3-ol, the first pi-comolar D5-selective dopamine-receptor antagonist. J Med Chem. 2006; 49: 2110-6
    CrossrefPubMedGoogle Scholar
  • 28 Enzensperger C, Gornemann T, Pertz HH, Lehmann J. Dopamine/serotonin receptor ligands. Part 17: A cross-target SAR approach: affinities of azecine-styled ligands for 5-HT(2A) versus D(l) and D(2) receptors. Bioorg Med Chem Lett. 2008; 18 (13) 3809-13
    CrossrefPubMedGoogle Scholar
  • 29 Enzensperger C, Kilian S, Ackermann M, Koch A, Kelch K, Lehmann J. Dopamine/serotonin receptor ligands. Part 15: Oxygenation of the benz-indolo-azecine LE 300 leads to novel subnanomolar dopamine D1/D5 antagonists. Bioorg Med Chem Lett. 2007; 17: 1399-402
    CrossrefPubMedGoogle Scholar
  • 30 Wernicke C, Schott Y, Enzensperger C, Schulze G, Lehmann J. Cytotoxicity of beta-carbolines in dopamine transporter expressing cells: structure-activity relationships. Biochem Pharmacol. 2007; 74: 1065-77
    CrossrefPubMedGoogle Scholar
  • 31 Abdel-Aziz H, Windeck T, Ploch M, Verspohl EJ. Mode of action of gingerols and shogaols on 5-HT3 receptors: binding studies, cation uptake by the receptor channel and contraction of isolated guinea-pig ileum. Eur J Pharmacol. 2006; 530: 136-43
    CrossrefPubMedGoogle Scholar
  • 32 Lopez-RodriguezMLMorcillo MJ, Benhamu B, Rosado ML. Comparative receptor mapping of serotoninergic 5-HT3 and 5-HT4 binding sites. J Comput Aided Mol Des. 1997; 11: 589-99
    CrossrefPubMedGoogle Scholar
  • 33 Heinzelmann RV, Anthony WC, Lyttle DA, Szmuszkovicz J. The synthesis of α-methyltryptophans and α-alkyltrypta-mines. J Org Chem. 1960; 25: 1548-58
    CrossrefPubMedGoogle Scholar
  • 34 Enzensperger C, Lehmann J. Dopamine/serotonin receptor ligands. 13: Homologization of a benzindoloazecine-type dopamine receptor antagonist modulates the affinities for dopamine D(l)-D(5) receptors. J Med Chem. 2006; 49: 6408-11
    CrossrefPubMedGoogle Scholar
  • 35 Enzensperger C, Müller FK, Schmalwasser B, Wiecha P, Traber H, Lehmann J. Dopamine/serotonin receptor ligands. 16.(1) Expanding dibenz[d,g]azecines to 11- and 12-membered homologues. Interaction with dopamine D(l)-D(5) receptors. J Med Chem. 2007; 50: 4528-33
    CrossrefPubMedGoogle Scholar