Abstract
3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878) is a novel compound with both 5-hydroxytryptamine (5-HT)1A agonism and 5-HT3 antagonism effects. We hypothesized that TZB-30878 might have benefits from these dual effects as a medication for diarrhea-predominant irritable bowel syndrome (d-IBS), and these studies were designed to confirm the pharmacological properties of TZB-30878 and its efficacy in an IBS-like animal model. The binding assays demonstrated that [3H]TZB-30878 selectively binds to human 5-HT1A and 5-HT3 receptors, with Kd values of 0.68 ± 0.03 and 8.90 ± 1.73 nM, respectively. Systemic administration of TZB-30878 inhibited 5-HT-induced bradycardia in a dose-dependent manner in rats. In behavioral assays TZB-30878 produced signs of 5-HT syndrome in rats. These results suggest that TZB-30878 has dual effects as a 5-HT1A receptor agonist and a 5-HT3 receptor antagonist. Finally, we evaluated the effects of TZB-30878 on wrap restraint stress-induced defecation in an IBS-like model in rats. TZB-30878 (1–10 mg/kg p.o.) normalized stress-induced defecation in a dose-dependent manner, whereas the 5-HT1A agonist tandospirone (30 and 100 mg/kg p.o.) and the 5-HT3 antagonist alosetron (1–10 mg/kg p.o.) did not show such effects. Furthermore, this efficacy of TZB-30878 was partly antagonized by a 5-HT1A antagonist, [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635). These results suggest that 5-HT1A receptor agonism and 5-HT3 receptor antagonism contribute to the efficacy of TZB-30878 in the IBS-like model. The efficacy of TZB-30878 supports the concept that the presence of both actions, namely 5-HT1A receptor agonism and 5-HT3 receptor antagonism, could be an important mechanism in the treatment of d-IBS.
Footnotes
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doi:10.1124/jpet.107.123729.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS: IBS, irritable bowel syndrome; 5-HT, 5-hydroxytryptamine, serotonin; d-IBS, diarrhea-predominant irritable bowel syndrome; TZB-30878, 3-amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one; GTPγS, guanosine 5′-[γ-thio]triphosphate; tandospirone, (1R*,2S*,3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3-bicyclo[2.2.1] heptanedicarboximide dihydrogen; alosetron, 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one; 8-OH-DPAT, 2-(N,N-di-n-propylamino)-8-hydroxy-1,2,3,4-tetrahydronaphthalene; WAY-100635, [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride; CHO, Chinese hamster ovary; BRL-43694, granisetron; HEK, human embryonic kidney; BJ, Bezold-Jarisch; CNS, central nervous system; 1-PP, 1-(2-pyrimidinyl)piperazine.
- Received April 3, 2007.
- Accepted May 30, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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