Description
Itopride, a gastroprokinetic benzamide derivative was launched in
Japan for the relief of gastrointestinal symptoms in patients with chronic gastritis.
ltopride is a dopamine D2-receptor antagonist that stimulates acetylcholine (Ach)
release on the postganglionic cholinergic neurons to cause Ach accumulation at
muscarinic receptors and, therefore, enhances Ach-induced gastric contractions. In
animal models, itopride was reported to increase GI transit and gastric emptying.
Chemical Properties
Crystalline Solid
Originator
Hokuriku (Japan)
Uses
Dopamine D2 receptor blockade,acetylcholinesterase inhibitor
Uses
Dopamine D2-receptor antagonist with anticholinesterase activity. Gastroprokinetic
General Description
Itopride hydrochloride is a new prokinetic drug.
Biochem/physiol Actions
Itopride hydrochloride enhances the gastrointestinal motility by blocking the activity of dopamine on the D2 receptors, on the post-synaptic cholinergic nerves and by inducing the liberation of acetylcholine in the myenteric plexus. It also inhibits the hydrolysis of the released acetylcholine with the help of acetylcholinesterase.
Synthesis
The general procedure for the synthesis of N-(4-(2-(dimethylamino)ethoxy)benzyl)-3,4-dimethoxybenzamide hydrochloride using etopride as a raw material is as follows: 16 kg of dry etopride and 56 kg of sec-butanol from Example 4 were added to a reactor and heated to 50-55°C until completely dissolved. 4.8 kg of 37% hydrochloric acid solution was added slowly and dropwise, during which the pH of the reaction mixture was monitored to ensure that it was below 2.0. The reaction mixture was stirred continuously at 50-55°C for at least 30 minutes. The mixture was then cooled to 15-25 °C and centrifuged. The precipitate was washed with 16.0 kg of sec-butanol. Finally, the product was dried at 70-80 °C to obtain 16.5 kg of itopride hydrochloride with HPLC purity of more than 99.8%. The yield of the reaction was 93.7% compared to etopride.
in vitro
itopride was found to inhibit both ache and horse serum butyrylcholinesterase (buche). the itopride ic50 against ache was, however, 100-fold less than that against buche. the recovery of ache activity inhibited by low dose of neostigmine was partial, but that inhibited by itopride was complete. double reciprocal plots showed that both vmax and km were affected by itopride, indicating a "mixed" type inhibition, although primarily being an uncompetitive one. in addition, the inhibitory effect of itopride on cholinesterase (che) activity in guinea pig gastrointestine was much weaker than that on pure ache [1].
in vivo
previoius animal study showed that in conscious dogs with implanted strain gauge force transducers, itopride could stimulate contractile activity in the gastrointestinal tract from stomach to colon. whereas, mosapride was able to stimulate contractile activity only in the gastric antrum and ileum. moreover, in rats s andguinea pig, itopride could accelerate colonic luminal transit, however, both mosapride and cisapride failed to enhance colonic transit. such findings suggested that itopride had a stimulatory action on propelling colonic luminal contents, colonic peristalsis, which was quite different from mosapride and cisapride [2].
References
[1] iwanaga y,kimura t,miyashita n,morikawa k,nagata o,itoh z,kondo y. characterization of acetylcholinesterase-inhibition by itopride. jpn j pharmacol.1994 nov;66(3):317-22.
[2] tsubouchi t,saito t,mizutani f,yamauchi t,iwanaga y. stimulatory action of itopride hydrochloride on colonic motor activity in vitro and in vivo. j pharmacol exp ther.2003 aug;306(2):787-93.
