PT  - JOURNAL ARTICLE
AU  - Satoru Tamaoki
AU  - Yukinao Yamauchi
AU  - Youichi Nakano
AU  - Sayuri Sakano
AU  - Akira Asagarasu
AU  - Michitaka Sato
TI  - Pharmacological Properties of 3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3<em>H</em>)-one (TZB-30878), a Novel Therapeutic Agent for Diarrhea-Predominant Irritable Bowel Syndrome (IBS) and Its Effects on an Experimental IBS Model
AID  - 10.1124/jpet.107.123729
DP  - 2007 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1315--1323
VI  - 322
IP  - 3
4099  - http://jpet.aspetjournals.org/content/322/3/1315.short
4100  - http://jpet.aspetjournals.org/content/322/3/1315.full
SO  - J Pharmacol Exp Ther2007 Sep 01; 322
AB  - 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.