5 '-N-substituted carboxamidoadenosines as agonists for adenosine receptors

Novel as well as known 5'-N-substituted carboxamidoadenosines were prepared via new routes that provided shorter reaction times and good yields. Bindi ng affinities were determined for rat A(1) and A(2A) receptors and human A( 3) receptors. EC50 values were determined for cyclic AMP production in CHO cells expressing human A(2B) receptors. On all receptor subtypes relatively small substituents on the carboxamido moiety were optimal. Selectivity for the Ag receptor was found for several analogues (1a, 1d, 1h, and 1k). On A (1) receptors a number of compounds, but not 5'-N-ethylcarboxamidoadenosine (NECA, 1b), showed small GTP shifts, which could be indicative of lower in trinsic activities at the A(1) receptor. At the A(2B) receptor, derivatives 1i-k with modified ethyl substituents had reduced activities compared to t he A(2B) reference agonist NECA (1b). Thiocarboxamido derivatives (8b and 8 c) displayed considerable although decreased A(2B) receptor activity. The X -ray structure determination of compound 8b was carried out. Due to intramo lecular hydrogen bonding between the carboxamido NH and the purine N3 in th e crystal structure, the ribose moiety of this compound is in a syn conform ation. However, theoretical calculations support that NECA (Ib), and less s o 8b, can readily adopt both the syn and the anti conformation, therefore n ot excluding the proposed anti mode of binding to the receptor.