Substituted benzamides. 1. Potential nondopaminergic antagonists of chemotherapy-induced nausea and emesis

Abstract

A series of new substituted benzamides has been synthesized and evaluated for dopamine antagonist activity and for antagonism of cisplatin-induced emesis in the dog and in the ferret. It was found that modification of the 2-methoxy substituent of metoclopramide was detrimental to dopaminergic D2 antagonism but not necessarily to antagonism of cisplatin-induced emesis. A number of analogues having a beta-keto, beta-hydroxy, beta-methoxy, beta-imino, or beta-unsaturated alkyloxy substituent instead of methoxy have shown equal or superior protection from emesis to that of metoclopramide. At the same time these compounds were found to be free of dopaminergic D2 antagonism in both in vitro ([3H]spiperone binding) and in vivo tests (rat catalepsy, antagonism of apomorphine-induced stereotypy in the rat, and apomorphine-induced emesis in the dog).

In vitro metabolic fate of alizapride: evidence for the formation of reactive metabolites based on liquid chromatography‐tandem mass spectrometry

“…(Torino, Italy); 6‐methoxy‐1 H ‐benzotriazole‐5‐carboxylic acid 1 and 6‐methoxy‐ N ‐{[1‐oxy‐1‐(prop‐2‐en‐1‐yl)pyrrolidin‐2‐yl]methyl}‐1 H ‐benzotriazole‐5‐carboxamide (diastereomers A 4 and B 5) were synthesized according to the procedure cited in the literature . 6‐Hydroxy‐ N ‐{[1‐(prop‐2‐en‐1‐yl)pyrrolidin‐2‐yl]methyl}‐1 H ‐benzotriazole‐5‐carboxamide 6 was synthesized as previously reported …”

“…[14] 6-Hydroxy-N-{[1-(prop-2-en-1-yl)pyrrolidin-2-yl]methyl}-1H-benzotriazole-5-carboxamide 6 was synthesized as previously reported. [15]…”

Erythromycin in the Short- and Long-term Control of Dyspepsia Symptoms in Patients with Gastroparesis

“…It has antiemetic effects related to central dopamine (D2) and serotonin (5-HT3) receptor antagonism and prokinetic activity related to 5-HT4 receptor facilitation of acetylcholine release from myenteric cholinergic neurons, dopamine (D2) receptor antagonism in the myenteric plexus, and sensitization of gut smooth muscle muscarinic receptors. [10][11] Side effects including drowsiness, lassitude, agitation, and anxiety occur in up to 20% of the patients. 12 Furthermore, metoclopramide can cause severe central nervous system side effects including acute dystonic reactions, akathisia, tardive dyskinesia and drug-induced Parkinsonism, some of which may be irreversible.…”

Management of the Patient with Gastroparesis

“…1, 2001 teric cholinergic neurons (5-HT 4 receptor), to dopamine D2 receptor antagonism in the myenteric plexus, and to direct smooth muscle contraction via muscarinic receptor sensitization. 20,21 Specific clinical effects of metoclopramide include increased esophageal contractions, improved antral contractions, decreased pyloric and duodenal tone, increased small bowel motility, and improved gastric emptying. 22,23 It is the only Food and Drug Administrationapproved agent for diabetic gastroparesis in this country.…”