Doxofylline interacts with adenosine receptors differently than theophylline

98

Pharmacological Research Communications, Vo/. 20, Supplement//, 1988

I)(~FYLLINE INTERAC_T5WITH ADENOSINEREC[PTO.~_DIFFERENTLYTHANTHEOPHYLL~_L~_ R. Cirillo, D. ~rone*, J.S. Frenzone ABC Ptmrmeco-Tox~cologicel Research Leboretor~e~ o Turin (It~lg) * Istituto "Antoine H~rxer" RBM, Colleretto {;iaco~a - Turin (ital g) Keg vords : adenosine receptors, xanthine~, asthma, brai n, ~triatum The brone,hodflatator, aotivit9 in rr~th91xanthine anti~'thmat~ drugs is accompanied ~

mafl~j

extral~imonarg side-effects that are both central (increased locomotor actiYitg, convulsions, tremors, anxietg) and peripheral (inorHsed d'~resis and natr"iuresis, release of free fatt 9 aoMs ar~ vasoconstr~tk)n, increased a~iditg and yolume of gastric secretion) whose apparition may c~rrelated to the interaction of these drugs ~th k l -

and A2-adenosine receptors, while the

bromhodflator and antibronchospastic a~ti~t9 seems to be mediated different~ (1,2). Doxofgllir~ (DOXO)is a methvlxanthine deriYative that has been introduced in theral~J recentlg and that does not induce the usual sklo--effeots of theolg~lline (THEO) even though it has s~ilar bronohodflator properties (3). The aim of this stud9 was the evaluation of the possibfliflj that the absence of

methglxanthin~-likecentral and peripheralside-effectsafter COXO administrationis linked(o a Tackof affinit~lbetween thisdrug and k l - and k2-adenosinereceptors. At-~lehosine receptors were labelled ~'ith l~-¢9¢1ohexvl-3H-adenosine (3H-CHA, I nil) in svnaptosoma) membrane prepared from guinea-pig brain; k2-adenosine receptors were obtained from rat striatum and labelled with 5'-N-ethg~boxamido-adenosine (Z~i-PECA, 4 nil) in the presence of SO nH N6-cgclopenty],xlerx)sinein order to seleotNehj exclude the binding of 3H-NECk to Al-sftes. The aff'mit9 of DOXO, THEO, bamifgTline and enprofglline was determined through their respoctive IC50 whi~ are respocfive~ : 119,000, 18,000, 19,000, and 114,000 ~ with 3H-CHA and 212,000, 25,000, 131 ,CO0 and 81,000 nH with 3H-I~CA. Our data defmx~rate that the affinity of DOXOwith adenosinereceptors is as low and the tC,50 va~.,~s are as hRh that 'thev do not possessan9 pharmacological meaning. In fact, the JCSOYa~esof DOXOare ~JCh higher than the corresponding pt~;rnat;~ a~J tissue concentrations at therapeut';c doses of" DOXO (4). In addfUon, these data can explain the absenceof well-known meth~j1xanthineside-effects after the administraHon of t~erapeutic doses of D~O and demonstrate that the antl"oronchospastic and brond~lflator acti~it9 and the antagonism to adenosinereceptors are not necessari~j associated(5). REFERENCES I) Dal9 d.~. et al.,LifeSci., 1981,28, 2083 2) FredhoklnB.B., ~ t a Pled.Scand., 1985, 21"7, 149 3) Franzoned.S. et al., I1Farmaco Ed. So., 1981,36, 201 4) Franzone J.S. et al.,11FarrnacnEd. Sc., 1981,36,220 5) Persson C.6.A. et al., ~ t a PharmacoT.et Tox-i¢ol., 1981,49, 3t7