Functionalized congeners of 1,3-dialkylxanthines: preparation of analogues with high affinity for adenosine receptors.
A series of functionalized congeners of 1,3-dialkylxanthines has been prepared as adenosine receptor antagonists. On the basis of the high potency of 8-(p-hydroxyphenyl)-1,3-dialkylxanthines, the parent compounds were 8-[4-[(carboxymethyl)oxy]phenyl] derivatives of theophylline and 1,3-dipropylxanthine. A series of analogues including esters of ethanol and N-hydroxysuccinimide, amides, a hydrazide, an acylurea, and anilides were prepared. The potency in blocking A1-adenosine receptors (inhibition of binding of N6-[3H]cyclohexyladenosine to brain membranes) and A2-adenosine receptors (inhibition of 2-chloroadenosine-elicited accumulations of cyclic AMP in brain slices) was markedly affected by structural changes distal to the primary pharmacophore (8-phenyl-1,3-dialkylxanthine). Potencies in the dipropyl series at the A1 receptor ranged from Ki values of 1.2 nM for a congener with a terminal amidoethyleneamine moiety to a Ki value of 58 nM for the parent carboxylic acid to a Ki of 96 nM for the bulky ureido congener. Certain congeners were up to 145-fold more active at A1 receptors than at A2 receptors. Various derivatives of the congeners should be useful as receptor probes and for radioiodination, avidin binding, and preparation of affinity columns.
Jacobson
K A
KA
Kirk
K L
KL
Padgett
W L
WL
Daly
J W
JW
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004951:Esterification; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D011983:Receptors, Purinergic; D013329:Structure-Activity Relationship; D013806:Theophylline; D014966:Xanthenes / Q000138:chemical synthesis / Q000494:pharmacology*; D014970:Xanthines
D011956:Receptors, Cell Surface; D011983:Receptors, Purinergic; D014966:Xanthenes; D014970:Xanthines; C027513:N(6)-cyclohexyladenosine; D013806:Theophylline; D000241:Adenosine; C046489:1,3-dipropylxanthine