Genotoxicity of 2-(3-chlorobenzyloxy)-6-(piperazinyl)pyrazine, a novel 5-hydroxytryptamine2c receptor agonist for the treatment of obesity: Role of metabolic activation

Drug Metabolism and Disposition

Volumn 35, Issue 6, 2007, Pages 848-858

  Kalgutkar, Amit S ^a   Dalvie, Deepak K ^b   Aubrecht, Jiri ^a   Smith, Evan B ^b   Coffing, Stephanie L ^a   Cheung, Jennifer R ^a   Vage, Chandra ^a   Lame, Mary E ^a   Chiang, Phoebe ^a   McClure, Kim F ^a   Maurer, Tristan S ^a   Coelho Jr , Richard V ^a   Soliman, Victor F ^a   Schildknegt, Klaas ^a  

^a PFIZER INC   (United States)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

2 (3 CHLOROBENZYLOXY) 6 (PIPERAZINYL)PYRAZINE; 6 (3 CHLOROBENZYLOXY) N (2 AMINOETHYL)PYRAZIN 2 AMINE; CYANIDE; DRUG METABOLITE; GLUTATHIONE; METHOXYAMINE; PYRAZINE DERIVATIVE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; SEROTONIN AGONIST; UNCLASSIFIED DRUG;

AMES TEST; ARTICLE; BACTERIAL STRAIN; DNA BINDING; DOSE RESPONSE; DRUG STRUCTURE; DRUG SYNTHESIS; GENOTOXICITY; HYDROXYLATION; METABOLIC ACTIVATION; OBESITY; PRIORITY JOURNAL; RADIOACTIVITY; REVERTANT;

BIOTRANSFORMATION; MUTAGENICITY TESTS; OBESITY; PIPERAZINES; PYRAZINES; RECEPTOR, SEROTONIN, 5-HT2C; SALMONELLA TYPHIMURIUM;

RATTUS; SALMONELLA;

EID: 34249103662     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.106.013649     Document Type: Article

References (25)

1. Ames AA, Nelson SD, Lovenberg W, and Sasame HA (1977) Metabolic activation of parachloroamphetamine to a chemically reactive metabolite. Commun Psychopharmacol 1:455-460.
2. Baillie TA and Davis MR (1993) Mass spectrometry in the analysis of glutathione conjugates. Biol Mass Spectrom 22:319-325.
3. Bickerdike MJ (2003) 5-HT2C receptor agonists as potential drugs for the treatment of obesity. Curr Top Med Chem 3:885-897.
4. Bodell WJ, Ye Q, Pathak DN, and Pongracz K (1998) Oxidation of eugenol to form DNA adducts and 8-hydroxy-2′-deoxyguanosine: role of quinone methide derivative in DNA adduct formation. Carcinogenesis 19:437-443.
5. Bolton JL, Acay NM, and Vukomanovic V (1994) Evidence that 4-allyl-o-quinones spontaneously rearrange to their more electrophilic quinone methides: potential bioactivation mechanism for the hepatocarcinogen safrole. Chem Res Toxicol 7:443-450.
6. Bolton JL, Turnipseed SB, and Thompson JA (1997) Influence of quinone methide reactivity on the alkylation of thiol and amino groups in proteins: studies utilizing amino acid and peptide models. Chem-Biol Interact 107:185-200.
7. Chen LJ, Hecht SS, and Peterson LA (1995) Identification of cis-2-butene-1,4-dial as a microsomal metabolite of furan. Chem Res Toxicol 8:903-906.
8. Chen LJ, Hecht SS, and Peterson LA (1997) Characterization of amino acid and glutathione adducts of cis-2-butene-1,4-dial, a reactive metabolite of furan. Chem Res Toxicol 10:866-874.
9. Clark NG and Cawkill E (1975) Reaction between cyanide ion and nitrons: novel imidazole synthesis. Tetrahedron Lett 31:2717-2720.
10. Dunlop J, Sabb AL, Mazandarani H, Zhang J, Kalgaonker S, Shukhina E, Sukoff S, Vogel RL, Stack G, Schechter L, et al. (2005) WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH- cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a novel 5-hydroxytryptamine 2C receptor-selective agonist with anorectic activity. J Pharmacol Exp Ther 313:862-869.
11. Heisler LK, Chu HM, and Tecott LH (1998) Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice. Ann NY Acad Sci 861:74-78.
12. Hoyer D, Hannon JP, and Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533-554.
13. Kim BS and Margolin BH (1999) Prediction of rodent carcinogenicity utilizing a battery of in vitro and in vivo genotoxicity tests. Environ Mol Mutagen 34:297-304.
14. Kim T-R, Kim Y-H, and Pyun S-Y (1999) Kinetic studies on the addition of potassium cyanide to α,N-diphenylnitrone. Bull Korean Chem Soc 20:712-714.
15. Kimura Y, Hatanaka K, Naitou Y, Maeno K, Shimada I, Koakutsu A, Wanibuchi F, and Yamaguchi T (2004) Pharmacological profile of YM348, a novel, potent and orally active 5-HT2C receptor agonist. Eur J Pharmacol 483:37-43.
16. Maron DM and Ames BN (1984) Revised methods for the Salmonella mutagenicity test. Mutat Res 113:173-215.
17. Masand PS (2000) Weight gain associated with psychotropic drugs. Expert Opin Pharmacother 1:377-389.
18. Modica E, Zanaletti R, Freccero M, and Mella M (2001) Alkylation of amino acids and glutathione in water by o-quinone methide: reactivity and selectivity. J Org Chem 66:41-52.
19. Nonogaki K, Strack AM, Dallman MF, and Tecott LH (1998) Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med 4:1152-1156.
20. Schnetz-Boutaud N, Daniels JS, Hashim MF, Scholl P, Burrus T, and Marnett LJ (2000) Pyrimido[1,2-α]purin-10(3H)-one: a reactive electrophile in the genome. Chem Res Toxicol 13:967-970.
21. Szeliga J and Dipple A (1998) DNA adduct formation by polycyclic aromatic hydrocarbon dihydrodiol epoxides. Chem Res Toxicol 11:1-11.
22. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, and Julius D (1995) Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature (Lond) 374:542-546.
23. Vickers SP and Dourish CT (2004) Serotonin receptor ligands and the treatment of obesity. Curr Opin Investig Drugs 5:377-388.
24. von Meyenburg C, Langhans W, and Hrupka BJ (2003) Evidence that the anorexia induced by lipopolysaccharide is mediated by the 5-HT2C receptor. Pharmacol Biochem Behav 74:505-512.
25. Zeiger E (1998) Identification of rodent carcinogens and noncarcinogens using genetic toxicity tests: premises, promises, and performance. Regul Toxicol Pharmacol 28:85-95.