Recurrent apnea is commonly observed in premature infants and may predispose some infants to lethal apneic episodes. Theophylline and caffeine are used routinely in the prevention of recurrent apnea, due to their stimulant effects on the respiratory center. The beneficial effects of these methylxanthines (MX) are complicated by the risk of cardiac and central nervous system (CNS) toxicity. Structure-activity studies have revealed that alkyl substitution at the 1-position of the xanthine nucleus is required for adenosine antagonism and CNS excitation, while alkyl substitution at the 3-position increases bronchodilator potency independent of adenosine antagonism. Comparable studies have not been conducted for the respiratory stimulant effects of MXs. The hypothesis to be tested in the present proposal is that the respiratory stimulant effects of MXs can be separated from the adverse effects by removal or alteration of methyl groups on the xanthine nucleus. To test this hypothesis, a series of methyl- and propyl- substituted xanthines will be systematically studied for stimulation of respiratory rate and volume in newborn rats using a body plethysmograph method. By generating dose-response curves for each of these compounds, their potencies can be compared. At least one novel analog, 1-propylxanthine, will be synthesized for these studies. Subsequent experiments will be carried out using those compounds which appear to be the most selective for the respiratory center. These compounds will be tested in newborn rats for their ability to reverse adenosine- and hypoxia-induced apnea. The results of these studies should indicate whether or not MX-induced respiratory stimulation is mediated by adenosine receptor antagonism. The ventilatory response to carbon dioxide inhalation will be studied in order to further elucidate the central mechanisms of MX-induced respiratory stimulation. Future experiments will examine respiratory, cardiac and CNS effects of these and other novel xanthine analogs. A long-term goal is to develop selective respiratory stimulants which are safe and effective for the treatment of recurrent apnea of prematurity and the prevention of sudden infant death.
