Journal of Pharmaceutical Investigation

The Korean Society of Pharmaceutical Sciences and Technology (한국약제학회)
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Pharmacokinetics and Bioavailability of New Synthetic 5-HT2C Agonists, KKHQ80109 and KKHQ80114, in Sprague-Dawley Rats

  • Im, Hye-Yeon (Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology) ;
  • Choo, Hyun-Ah (Center for Chemoinfomatics Research, Korea Institute of Science and Technology) ;
  • Pae, Ae-Nim (Center for Chemoinfomatics Research, Korea Institute of Science and Technology) ;
  • Kwon, Oh-Seung (Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology)
  • Published : 2009.10.20
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Abstract

5-HT$_{2C}$ receptors have been considered as therapeutic targets for the treatment of various central nervous system disorders such as depression, anxiety, epilepsy, schizophrenia and sleep disorders. We chemically synthesized KKHQ80109 (K09) and KKHQ80114 (K14), selective 5-HT$_{2C}$ agonists, with the purpose of developing therapeutic agents for the treatment of obesity. The objective of this work is to investigate pharmacokinetic parameters and bioavailability of K09 and K14 in rats given orally or intravenously. Oral administration of 20 mg/kg K09 results in 4.11 hr of the terminal half-life and 89.16 ng/mL of C$_{max}$ at 5.00 hr (T$_{max}$). The terminal half-life of K14 was 3.83 hr with 215.81 ng/mL of C$_{max}$ at 3.33 hr (T$_{max}$) after oral dosing of 20 mg/kg K14, indicating that K14 is more rapidly absorbed than K09. Bioavailability showed 0.17-0.21 for K09 and 0.19-0.23 for K14. Urinary excretion of parent K09 and K14 was less than 1%, indicating that K09 and K14 undergo very extensive hepatic metabolism.

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References

  1. D. Hoyer, D.E. Clarke, J.R. Fozard, P.R. Hartig, G.R. Martin, E.J. Mylecharrane, P.R. Saxena and P.P.A. Humphrey. Internation Union of Pharmacology classification of receptors for hydroxytryptamine (serotonin). Pharmacol. Rev., 46, 157-204 (1994).
  2. D. Hoyer and G.R. Martin. 5-HT receptor classification and nomenclature: towards a harmonization with the human genome. Neuropharmacology, 36, 419-428 (1997). https://doi.org/10.1016/S0028-3908(97)00036-1
  3. G. Di Giovanni, V. Matteo, M. Pierucci, A. Benigno and E. Espoito. Central serotoinin 2C receptor: from physiology to pathology. Curr. Top Med. Chem., 6, 1909-1925 (2006). https://doi.org/10.2174/156802606778522113
  4. M.G. Frank, M.P. Stryker and L.H. Tecott. Sleep and sleep homeostasis in mice lacking the 5-HT2c receptor. Neuropharmacology , 27, 869-873 (2002). https://doi.org/10.1038/S0893-133X(02)00353-6
  5. M. Issac. Serotonergic 5-HT2c receptors as a potential therapeutic target for the design of antiepileptic drugs. Curr. Top Med. Chem., 5, 59-67 (2005). https://doi.org/10.2174/1568026053386980
  6. M.J. Millan. Serotonin 5-HT2c receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. Therapie, 60, 441-460 (2005). https://doi.org/10.2515/therapie:2005065
  7. L.H. Tecott, L.M. Sun, S.F. Akana, A.M. Strack, D.H. Lowenstein, M.F. Dallman and D. Julius. Eating disorders and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature, 374 (6522), 542-546 (1995). https://doi.org/10.1038/374542a0
  8. L.H. Tecott and L. Abdallah. Mouse genetic approaches to feeding regulation: serotonin 5-HT2C receptor mutant mice. CNS Spectr., 8, 584-588 (2003).
  9. R.A.H. Adan, L.J.M.J. Vanderschuren and S.E. La Fleur. Antiobesity drugs and neural circuits of feeding. Trends .Pharmacol. Sci., 29 (4), 208-217 (2008). https://doi.org/10.1016/j.tips.2008.01.008
  10. D. Murphy and K.P. Lesch. Targeting the murine serotonin transporter: insights into human neurobiology (Reviews). Nature Rev./Neurosci., 9, 85-96 (2008). https://doi.org/10.1038/nrn2284
  11. A.N. Pae, H. Choo, Y.S. Cho, S. A. Jun, H.J. Cho, W.K. Park and J.M. Kim, Novel sulfonamide derivatives as 5-HT2a/2c receptors antagonist and serotonin reuptake inhibitors and preparation thereof. Patent submitted (2009).
  12. J.T. DiPiro, W.J. Spruill, W.E. Wade, R.A. Blouin and J.M. Pruemer. Half-life, elimination rate and AUC: In Concept in Clinical Pharmacokinetics (4th Ed.), American Society of Health-System Pharmacists, pp. 29-44 (2005).
  13. S.M. Bromidge, S.E. Clarke, T. Gager, K. Griffith, P. Jeffrey, A.J. Jennings, G.F. Joiner, F.D. King, P.J. Lovell, S.F Moss, H. Newman, G. Riley, D. Rogers, C. Routledge, H. Serafinowska and D.R. Smith. Phenyl benzenesulfonamides are novel and selective $5-HT_6$ antagonists: Identification of N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134). Bioorg. Med. Chem. Lett. 11, 55-58 (2001). https://doi.org/10.1016/S0960-894X(00)00597-7