8-Dimethylamino-1-methyladenine, a novel potent antagonist of the 1-methyladenine receptor in starfish oocytes.

Starfish oocytes are naturally arrested in the late G2 phase of the first meiotic division. The follicle-cell-derived hormone, 1-methyladenine, is responsible for highly synchroneous induction of oocyte maturation. A series of systematically modified 1-methyladenine analogues was used to map the essential molecular interactions between 1-methyladenine and its stereospecific receptors, which are localized on the oocyte plasma membrane. The earlier hypothesis about structure/activity relationships has been confirmed. Quantum-chemical calculations indicated additional dipole-dipole interactions and presumably a charge-transfer interaction, with the nucleobase as pi-electron donor. Among the 49 compounds tested, a series of novel inhibitors of 1-methyladenine-induced maturation was found. With the synthesis of 8-dimethylamino-1-methyladenine (concentration for 50% inhibition 1 microM), a very potent antagonist of the natural hormone was obtained which may become an important tool for investigating the mechanism of 1-methyladenine-induced maturation of the starfish oocytes, an important model for cell-cycle-control studies. The results are discussed in the context of preexisting biological data. In conclusion, we propose a modified model of the molecular interactions between 1-methyladenine and its receptor.