Based on our previous results on the potent antagonist effect of 1H,3H-pyrido[2,1-f]purine-2,4-diones at the human A(3) adenosine receptor, new series of this family of compounds have been synthesized and evaluated in radioligand binding studies against the human A(1), A(2A), A(2B), and A(3) receptors. A remarkable improvement in potency, and most noticeable, in selectivity has been achieved, as exemplified by the 3-cyclopropylmethyl-8-methoxy-1-(4-methylbenzyl)-1H,3H-pyrido[2,1-f]purine-2,4-dione (10) that combines a very high affinity at hA(3) (K(i)=2.24 nM), with lack of affinity for the A(1), A(2A), and A(2B) receptors. On the basis of the published hA(3) receptor model (PDB 1OEA), molecular modeling studies, including molecular dynamics (MD) simulations, have been performed to depict the binding mode of the 1 H,3H-pyrido[2,1-f]purine-2,4-diones and to justify the selectivity against the other adenosine receptors. These studies have led to novel features of the cavity where our antagonists are bound so that the cavity is lined by the hydrogen-bonded Gln 167-Asn 250 pair and by the highly conserved Phe 168.

A Functional Screening of Adenosine Analogues at the Adenosine A 2B Receptor: A Search for Potent Agonists. -About 100 title compounds of type are tested. The 5'-N-substituted carboxamidoadenosines were the most potent ones; other ribose-modified derivatives display low to negligible activity. -(DE ZWART, M.; LINK, R.; VON FRIJTAG DRABBE KUENZEL, J. K.; CRISTALLI, G.; JACOBSON, K. A.; TOWNSEND-NICHOLSON, A.; IJZERMAN, A. P.; Nucleosides Nucleotides 17 (1998) 6, 969-985; Dep. Chem., Leiden Univ., NL-2300 RA Leiden, Neth.; EN)

nucleic acidsnucleic acids U 0700 -2002-Nitro Analogues of Adenosine and 1-Deazaadenosine: Synthesis and Binding Studies at the Adenosine A 1 , A 2A , and A 3 Receptor Subtypes.-The effect of a nitro group at the 2-position in adenosine analogues (V) and (XIII) together with receptor selective N-6 substituents on the affinity at the adenosine title receptor is investigated. An efficient nitration reagent consists of a mixture of tetrabutylammonium nitrate and trifluoroacetic anhydride. Competing methanolysis of the nitro group of (III) is reduced to a minor process. For the preparation of parent compound (IX), a three-step procedure avoids the use of ammonia. The analogues (V) and (XIII) show good adenosine receptor activity, demonstrating directable selectivity for the A 1 , A 2A , and A 3 adenosine receptor subtypes.-(WANNER, MARTIN J.; VON FRIJTAG DRABBE KUENZEL, JACOBIEN K.; IJZERMAN, AD P.; KOOMEN, GERRIT-JAN;