COMPARATIVE STRUCTURE-AFFINITY RELATIONS BY MTD FOR BINDING OF CYCLOADENOSINE MONOPHOSPHATE DERIVATIVES TO PROTEIN-KINASE RECEPTORS

A ''testkit'' series of 27 derivatives of cAMP with various substituen ts in position 1, 2, 6 and 8 and within the purine cycle, thiophosphor ic acid derivatives (with equatorial or axial S-atom) also included, w ere used to map four receptor sites of the R-subunit of cAMP dependent phosphokinases I and II, namely labile and stable receptors AI, BI, A U and BII. A QSAR by the MTD method was applied for the four series of activities, together with the relative nitrogen base hydrophobicity ( IgK(w)), electric charge of the position 6-substituent (qN(6)(+)) and an indicator variable (delta = 1 for equatorial thiophosphoric derivat ives). Correlation coefficients between r = 0.836 and 0.948 were obtai ned and the reliability of QSAR results was tested by a cross validati on-like procedure. Characteristic steric features (concerning the effe cts of substituents in different nitrogen-base positions) were separat ely obtained for each receptor. For AI and BI receptor there is a nega tively charged receptor group interacting with substituents in positio n 6 of cAMP derivatives. BI and BII receptors are of a marked hydropho bic character. Thiophosphoric acid derivatives, especially those with equatorial S-atom, have a decreased affinity for all four receptors. T he results are compared with other QSAR studies of our group, concerni ng different series of cAMP derivatives.