Conformationally restricted analogues of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide

Conformationally restricted analogues of the selective partial muscarinic agonist N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM 5; 2) were synthesized. The compounds were tested for muscarinic and antimuscarinic activity in the isolated guinea pig ileum and in intact mice. They were found to be moderately potent muscarinic antagonists or weak partial agonists. The new compounds were less potent than 2 in inhibiting (-)-[3H]-N-methylscopolamine binding in the rate cerebral cortex. Thus, structural modifications of 2 in which part of the amide moiety has been connected with the methyl group in the butynyl chain to form a five-membered ring decrease affinity and in most cases abolish efficacy.     

Pharmacological properties of fluphenazine-mustard, an irreversible calmodulin antagonist

We describe an improved synthesis and properties of fluphenazine-mustard, a potent phenothiazine having an alkylating chlorethylamine chain in its structure. The drug possesses anticalmodulin activity equivalent to the parent compound, but unlike fluphenazine dihydrochloride, the mustard derivative irreversibly antagonizes the ability of calmodulin to activate cyclic nucleotide phosphodiesterase. This property is partially calcium-dependent and can be overcome by coincubation with excess fluphenazine dihydrochloride. The compound irreversibly inactivated calmodulin when incubated with intact cells and caused single-stranded breakage of DNA. Fluphenazine-mustard possesses potent antiproliferative and cytotoxic properties against malignant cell lines that are likely to be mediated through both of these actions.     

Congenital esophageal cysts in adults

Sixteen adult patients with congenital esophageal cysts were operated on between 1957 and 1979. Preoperatively, 7 patients (44%) were asymptomatic and the cyst was found incidentally on a routine chest roentgenogram. Esophageal symptoms were present in only 3 patients (19%), whereas most symptomatic patients had precordial sensations or arrhythmias. A correct preoperative diagnosis was made in only 1 patient. After enucleation of the cyst, preoperative symptoms were alleviated in all patients and short-term results were excellent. However, long-term follow-up 13.2 +/- 5.6 (+/- standard deviation) years later revealed moderate reflux in 9 (64%) of the surviving 14 patients. During esophagoscopy, macroscopic esophagitis was found in 12 (92%) of 13 patients. On histological examination of specimens obtained by forceps biopsy, esophagitis was present in 10 (77%) of 13 patients and included Barrett esophagus in 2. We conclude that, despite excellent early results, long-term follow-up of patients who undergo operation for congenital esophageal cysts is indicated because of the increased incidence of reflux esophagitis.