title: Tetrahydroberberine, an isoquinoline alkaloid isolated from corydalis tuber, enhances gastrointestinal motor function.
abstract: 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 D(2) (pK(i) = 6.08) and 5-HT(1A) (pK(i) = 5.38) receptors but moderate to no affinity for other relevant serotonin receptors (i.e., 5-HT(1B), 5-HT(1D), 5-HT(3), and 5-HT(4); pK(i) < 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-HT(1A) antagonist, and N(ω)-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 D(2) receptor antagonist and 5-HT(1A) receptor agonist properties, has significant potential as a therapeutic for treatment of FD.
authors.affiliation: R&D Center, Dong-A Pharmaceutical Co, Ltd, Yongin, South Korea.
authors.forename: Tae Ho
authors.initials: TH
authors.lastname: Lee
authors.forename: Ki Hyun
authors.initials: KH
authors.lastname: Kim
authors.forename: Sung Ok
authors.initials: SO
authors.lastname: Lee
authors.forename: Kang Ro
authors.initials: KR
authors.lastname: Lee
authors.forename: Miwon
authors.initials: M
authors.lastname: Son
authors.forename: Mirim
authors.initials: M
authors.lastname: Jin
mesh_terms: D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D031311:Corydalis / Q000737:chemistry*; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004415:Dyspepsia / Q000150:complications / Q000188:drug therapy; D004576:Electromyography; D005748:Gastric Fundus / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D018517:Plant Roots / Q000737:chemistry; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical
chemical_list: D010936:Plant Extracts; D001599:Berberine; C004645:canadine