Abstract

A new class of inhibitor of phosphodiesterases is represented by 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62711). This compound enhances the magnitude of accumulations of cyclic 3',5'-AMP elicited by norepinephrine, isoproterenol, histamine, and adenosine in rat cerebral cortical slices and by veratridine in rat cerebellar slices and, in addition, increases basal levels of cyclic AMP in both cortical and cerebellar slices. Increases in intracellular levels of cyclic AMP in brain slices elicited by ZK 62711 do not appear to involve enhanced "release" of adenosine, since both basal and norepinephrine-elicited accumulations of cyclic AMP are increased by ZK 62711 in the presence of exogenous adenosine deaminase. ZK 62711 has little effect on levels of cyclic GMP in cortical or cerebellar slices. In rat cerebral homogenates ZK 62711 inhibits soluble and particulate cyclic AMP phosphodiesterases but is less potent with respect to cyclic GMP phosphodiesterases. At low concentrations it is 100 times more potent than a structurally related phosphodiesterase inhibitor, Ro 20-1724, with respect to the calcium-dependent cyclic AMP phosphodiesterase, and in brain slices it is similarly 100 times more potent in enhancing accumulations of cyclic AMP elicited by norepinephrine.