Date of Award
1969
Degree Type
Thesis
Degree Name
Master of Science in Pharmacology
Department
Pharmacology
First Advisor
John J. DeFeo
Abstract
Several 1-alkylbenzoylpyridinium halides containing alkyl side chains of one to fifteen carbons were screened for pharmacological activity. A comparison of potency was based on the ability to produce mortality in 50 percent of mice (LD 5D). The following parameters were investigated in a select number of compounds representative of the series: acute intraperitoneal LD50 in rats; EDSO (hypotensive) in rats; effects on the autonomic nervous system of anesthetized cats and dogs as indicated by alteratio11s in blood pressure; effects en the nictitating membrane in anesthetized cats; direct effects upon blood vessels employing hind quarter perfusion in intact rats; effects on the isolated perfused guinea pig heart. In mice the trend of acute intraperitonsal toxicity was biphasic. ~he methyl salts were the least toxic , while toxicity sharply increased with the ethyl salts. As the carbon substitution increased to seven, toxicity decreased. Further carbon substitution led to a progressive increase in toxicity. Although fewer compounds were tested in rats, the LD50’s approximately paralleled those of the mice. 3-Benzoyl-1-ethylpyridinium iodide (3-C2-I), 3-benzoyl-1-octylpyridinium bromide (3-CB-Br), and 3-benzoyl-1-pentadecylpyridinium bromide ( 3-C15-Br) produced hypotensive effects in anesthetized rats. The ED50 (hypotensive) increased in that order. Demonstration of hypotensive responses in anesthetized rats led to an investigation of the mechanism of this action& Decreased responses to carotid occlusion and vaga l stimulation 2nd increased responses to injected epinephrine in anesthetized cats and dogs suggested th a t the 3-C2-I and 3-CB-Br exerted a hypotensive response through ganglioplegia. 3-CB-Br was more potent than 3-C2-I. Further testing of 3-C15-~ was discontinued at this time as respiratory failure followed by cardiac arrest occurred, apparently due to excessive quantities of fluid in the respiratory passages. 3-Benzoyl-1-dodecylpyridinium bromide also elicited this response. The ability of 3-C2-I and 3-CB-Br to block the normal response of the nictitating membrane in cats by electrical stimulation of the pre~ ganglionic cervical sympathetic nerve was tested 3-CB-Br was more potent than 3-C2-I in this test. The flow rates of perfusions of the hind quarter vasculature of the intact rats were unaffected by doses up to the equivalent ED 50 (hypotensive) 3-C2-I and 3-CB-Br showed cardiodepressant and cardiotoxic effects on the isolated guinea pig heart, although a direct dose effect relationship could not be shown. 3-CB-Br was more potent than 3-C2-I in producing cardiac arrest. The results of these experiments support the hypothesis that 3-C2-I and 3-CS-Br exert a hypotensive effect through ganglioplegia, unabetted by direct vasodilation. A depressant action on the heart may contribute to the hypotension induced by ganglioplegia.
Recommended Citation
Springfield, Angela Caretta, "Pharmacology of Some 1-Alkyl-3-Benzoylpyridinium Halides" (1969). Open Access Master's Theses. Paper 228.
https://digitalcommons.uri.edu/theses/228
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