Mapping the xanthine C8-region of the adenosine A1 receptor with computer graphics.
Substitution at the 8-position of 1,3-dipropylxanthines can lead to very potent and selective adenosine A1 antagonists. The xanthine C8-region was investigated in this study, using CAMM (computer-assisted molecular modeling). This region can be divided into two subregions with a considerable overlap in volume: a phenyl region which binds the flat substituents and a cycloalkyl region which binds the other substituents. The 8-phenyl-substituted derivatives bind with an N9-C8-Cl'-C2' dihedral angle of 220 degrees; this dihedral angle is 330 degrees for the 8-cycloalkyl-substituted derivatives. The lower affinity of C8-substituted 7-methyl-1,3-dipropylxanthines can be explained quantitatively with steric hindrance, which C8-substituents experience from the 7-methyl group in these conformations. The substitution pattern determines the affinity for 8-phenyl-substituted compounds for which the energy cost to reach the dihedral angle of 220 degrees is low, but has little influence otherwise. The affinity of the 8-cycloalkyl-1,3-dipropylxanthines is mainly volume dependent, because of a forbidden area near the cycloalkyl region.
Center for Bio-Pharmaceutical Sciences, Division of Medicinal Chemistry, Leiden, The Netherlands.
E M
EM
Van der Wenden
P J
PJ
Van Galen
A P
AP
IJzerman
W
W
Soudijn
D000818:Animals; D003196:Computer Graphics; D007700:Kinetics; D008956:Models, Chemical; D015394:Molecular Structure; D011487:Protein Conformation; D058914:Purinergic Antagonists; D051381:Rats; D011983:Receptors, Purinergic / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D058914:Purinergic Antagonists; D011983:Receptors, Purinergic; D014970:Xanthines