The influence of glucosidic conformation and charge distribution on activity of adenine nucleosides as presynaptic inhibitors of acetylcholine release.

The electrically stimulated guinea-pig ileum preparation was used to establish the potency of adenosine and a series of nucleoside analogs as presynaptic inhibitors of acetylcholine output and a rank order was obtained. 2-Chloroadenosine was the most potent compound studied (pD2 = 7.74), whereas inosine yielded the lowest measurable efficacy (pD2 = 3.66). The 8-substituted nucleotides studied were either poorly active or inactive. The Iterative Extended Huckel Theory method was used to calculate the total conformational energy of each analog as well as the electronic properties at key positions in purine moiety. Spectra relating conformation energy to the dihedral angle of rotation of the purine base about the glycoside bond permitted the preferred glycosidic conformation of each analog to be determined. Comparison of this conformational data, which indicated few strong conformational differences, with the biological efficacy did not permit an association between potency and stability in the glycosidic high anti conformation to be drawn. however, the inactivity of the adenine nucleotides with bulky substituents at position 8 may suggest involvement of the entire anti-high anti range as essential conformations. A possible association between activity and charge density at the purine N1 atom, for a subset of the nucleosides investigated, was seen. It is suggested that the accessibility of nucleosides to the entire anti-high anti conformational region is a permissive condition in addition to which other molecular characteristics play a role in determining activity at the presynaptic locus.