BRAIN DISTRIBUTION CHARACTERISTICS OF XANTHINE DERIVATIVES AND RELATION TO THEIR LOCOMOTOR-ACTIVITY IN MICE

The relationship between the brain distribution and motor activity in mice of the xanthines, theophylline, enprofylline, 1-methyl-3-propylxa nthine (MPX) and oxpentifylline was investigated. Their plasma protein binding and hydrophobicity were also examined. When these xanthines w ere administered orally, enprofylline and oxpentifylline had no effect on motor activity. While theophylline increased motor activity over 1 0 mg kg(-1), MPX caused a decrease in such activity over 10 mg kg(-1). The protein-binding behaviour varied among these xanthines and was cl osely related to their hydrophobicity, which is represented as a logar ithmic partition coefficient (log PC). MPX had the highest hydrophobic ity, while oxpentifylline had the lowest. Brain distribution character istics varied among these xanthines, with the rank order of their brai n penetration ratio, calculated as the ratio of brain to unbound plasm a concentrations, being theophylline > oxpentifylline > MPX > enprofyl line. The inhibition constants (K-i) for adenosine A(1) receptors and cyclic 3',5'-adenosine monophosphate (cAMP)-phosphodiesterase (PDE) of these xanthines were 4.46 and 134, > 1000 and 112, 26.4 and 49, and > 1000 and 111 mu M for theophylline, enprofylline, MPX, and oxpentifyl line, respectively. These findings suggest that the lack of effects of enprofylline and oxpentifylline on motor activity is probably due to their low brain penetration ratio or low adenosine A(1) affinity in co mparison with theophylline. The decrease in the motor activity by MPX may be, in part, mediated by cAMP or adenosine.