Pharmacological properties of 3-amino-5,6,7,8-tetrahydro-2-[4-[4-(quinolin-2-yl)piperazin-1-yl]butyl]quinazolin-4(3H)-one (TZB-30878), a novel therapeutic agent for diarrhea-predominant irritable bowel syndrome (IBS) and its effects on an experimental IBS model.
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-HT(3) 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 [(3)H]TZB-30878 selectively binds to human 5-HT(1A) and 5-HT(3) receptors, with K(d) 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-HT(1A) receptor agonist and a 5-HT(3) 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-HT(1A) agonist tandospirone (30 and 100 mg/kg p.o.) and the 5-HT(3) 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-HT(1A) antagonist, [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635). These results suggest that 5-HT(1A) receptor agonism and 5-HT(3) 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-HT(1A) receptor agonism and 5-HT(3) receptor antagonism, could be an important mechanism in the treatment of d-IBS.
Tamaoki
Satoru
S
Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd., 1604 Shimosakunobe, Takatsu-ku, Kawasaki 213-8522, Japan. tamaoki-s@aska-pharma.co.jp
Yamauchi
Yukinao
Y
Nakano
Youichi
Y
Sakano
Sayuri
S
Asagarasu
Akira
A
Sato
Michitaka
M
D000818:Animals; D003967:Diarrhea; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D052999:Quinazolinones / Q000494:pharmacology* / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D058825:Serotonin 5-HT1 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D018490:Serotonin Agents / Q000494:pharmacology*
C530714:3-amino-5,6,7,8-tetrahydro-2-(4-(4-(quinolin-2-yl)piperazin-1-yl)butyl)quinazolin-4-(3H)-one; D052999:Quinazolinones; D011804:Quinolines; D058825:Serotonin 5-HT1 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D018490:Serotonin Agents