Degree Name

Master of Science (MS)

Semester of Degree Completion

1989

Thesis Director

Kip L. McGilliard

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Abstract

Methylxanthines (MX), such as theophylline, are commonly used in the treatment of recurrent apnea due to their stimulant effects on the respiratory center. Structure-activity studies have demonstrated that substitution of alkyl groups on the 3-position of the xanthine nucleus results in increased bronchodilator potency, while substitution on the 1-position is important for adenosine antagonism and CNS stimulation. Three different alkylxanthines were studied to determine the structural requirements for respiratory stimulation. Respiratory rates and volumes were determined in 4- to 7-day-old rats using a volume displacement body plethysmograph. Measurements were made before and at 5 minute intervals after subcutaneous (s.c.) injection of drug. Theophylline (1,3-diMX, 10-40 mg/kg) increased minute ventilation (VE) in a dose-related mannor by as much as 45% over baseline. Increases were observed in both tidal volume (VT) and respiratory rate (f). 1-MX (20-40 mg/kg) increased VE by almost 20%, primarily by increasing f. 3-MX (10-20 mg/kg) failed to produce a significant change in VE. These data suggest that substitution at the 1-position of the xanthine nucleus is essential for respiratory stimulation. The effect may be further enhanced by substitution at the 3-position. The data further suggest that antagonism of adenosine receptors is necessary for alkylxanthine-induced respiratory stimulation.

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