Pj. Scammells et al., SUBSTITUTED 1,3-DIPROPYLXANTHINES AS IRREVERSIBLE ANTAGONISTS OF A(1)ADENOSINE RECEPTORS, Journal of medicinal chemistry, 37(17), 1994, pp. 2704-2712
This report describes the synthesis of 29 xanthines containing a chemo
reactive chloroaryl beta-chloroethylamino, alpha,beta-unsaturated carb
onyl bromoacetyl, 3-(fluorosulfonyl)benzoyl, or 4-(fluorosulfonyl)benz
oyl group as part of an exocyclic 1-, 3-, or 8-substituent. The xanthi
nes inhibited the binding of [H-3]-8-cyclopentyl-1,3-dipropylxanthine
([H-3]CPX) to the A(1) adenosine receptor (A(1)AR) of DDT1 MF2 cells a
t IC(50)s in the low-nanomolar to low-micromolar range. Seven of the 2
9 analogues irreversibly inhibited the binding of [H-3]CPX without cha
nging the K-D of that ligand; five were 1,3-dipropylxantines having th
e following reactive groups as 8-substituents: (bromoacetamido)methyl
(24), (bromoacetamido)ethyl (25), (bromoacetamido)propyl (26), [4-(flu
orosulfonyl)benzamido]methyl (33) or 3-[[4-(fluorosulfonyl)benzoyl]oxy
]cyclopentyl (42). Both luorosulfonyl)benzoyl]oxy]propyl]-1-propylxant
hine (53) and [3-[[4-(fluorosulfonyl)benzoyl]oxy]propyl]xanthine (55)
inhibited [H-3]CPX binding irreversibly. Five of the ligands, includin
g 26, 33 (IC50 = 49 mu M), and 53 (IC50 = 9 mu M), antagonized the bin
ding of [H-3]NECA to the A(2a)AR of PC12 cells, but unlike binding to
the A(1)AR, binding to the A(2a)AR was completely reversible. The pote
ncy of 33 (IC50 = 2 mu M, 72% loss of CPX binding at 1 mu M) and 53 (I
C50 - 0.01 mu M, 74% loss of CPX binding at 0.05 mu M) and their selet
ivity for the A(1)AR suggest that those two ligands may be useful in s
tudies of the structure and function of that receptor.