Molecular simulation of 8-styrylxanthines.

Regarding theophylline as representative xanthine derivative, it was shown that the net charges of various semiempirical quantum chemistry methods are transferable by scaling. PM3 should be preferred for calculation of xanthine derivatives. Molecular modelling indicated that there is a conformational similarity of the lead structure of xanthine and adenosine derivatives. The substituents bound to the C8 of xanthine and to the C2 of adenosine derivatives are involved in the discrimination into adenosine A 2 antagonists and agonists. The A 2 affinity of xanthines is mainly determined by the type of N7 substitution (hydrogen/methyl), the lipophilic substituent constant related to the C8 substituents, and the dipole moment of the molecules. To simulate chemically the A 1 affinity, a further term (lowest unoccupied molecular orbital energy) must be added. In addition, hydrogen-bonding forces were hypothesized using a newly synthesized 3,6-diaminocarbazole derivative as synthetic adenosine pseudoreceptor.