PT - JOURNAL ARTICLE AU - Tae Ho Lee AU - Ki Hyun Kim AU - Sung Ok Lee AU - Kang Ro Lee AU - Miwon Son AU - Mirim Jin TI - Tetrahydroberberine, an Isoquinoline Alkaloid Isolated from Corydalis Tuber, Enhances Gastrointestinal Motor Function AID - 10.1124/jpet.111.182048 DP - 2011 Sep 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 917--924 VI - 338 IP - 3 4099 - http://jpet.aspetjournals.org/content/338/3/917.short 4100 - http://jpet.aspetjournals.org/content/338/3/917.full SO - J Pharmacol Exp Ther2011 Sep 01; 338 AB - Because delayed gastric emptying and impaired gastric accommodation are regarded as pathophysiological mechanisms underlying functional dyspepsia (FD), prokinetics and fundic relaxants have been suggested as a new treatment for FD. We isolated tetrahydroberberine (THB), an isoquinoline alkaloid (5,8,13,13a-tetrahydro-9,10-dimethoxy-6H-benzo[g]-1,3-benzodioxolo[5,6-a]quinolizine) from Corydalis tuber, and found that it has micromolar affinity for dopamine D2 (pKi = 6.08) and 5-HT1A (pKi = 5.38) receptors but moderate to no affinity for other relevant serotonin receptors (i.e., 5-HT1B, 5-HT1D, 5-HT3, and 5-HT4; pKi < 5.00). Oral administration of THB not only resulted in significantly accelerated gastric emptying of normal rats in a bell-shaped relationship, with a maximal efficacy at a dose of 30 μg/kg, but also restored the delayed gastric emptying caused by apomorphine, which might be mediated by an antidopaminergic effect. Data from electromyography indicated enhanced motor function of the upper gastrointestinal tract by THB, which occurred through strengthening contractility and shortening the contraction interval. Furthermore, in rats stressed by repeated restraint, a significantly higher shift in the pressure-volume curve by THB (10 μg/kg, p < 0.05), which was inhibited by [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635), a 5-HT1A antagonist, and Nω-nitro-l-arginine methyl ester, a nitric-oxide synthase inhibitor but not a vasoactive intestinal peptide antagonist, was observed. Oral administration of THB resulted in a drastic increase of gastric accommodation in Beagle dogs. Area under the volume versus time curve was increased significantly by THB (30 μg/kg, p < 0.01) and comparable with that of sumatriptan (3 mg/kg), a potent fundic relaxant. Taken together, our data suggested that THB, with D2 receptor antagonist and 5-HT1A receptor agonist properties, has significant potential as a therapeutic for treatment of FD.