Unusual stereospecificity of the potential antidepressant rolipram on the cyclic AMP generating system from rat brain cortex.

Adrenoceptor sensitivity of central synapses is thought to be involved in regulation of mood. Persistent changes exceeding normal fluctuations conceivably could lead to disease states like manic-depressive illness. Several treatment regimens which affect mood in man reversibly alter the density of beta-adrenoceptors in animals in a time- and dose-dependent manner. Most prominently, many antidepressants which inhibit neurotransmitter uptake downregulate postsynaptic adrenoceptors, and thus diminish intracellular cyclic AMP formation elicited by noradrenaline. In addition, other modulations of presynaptic nerve activity, e.g. electroconvulsive shock or treatment with thyroid hormones, also cause adaptational responses at the postsynapse. In general, functional integrity of the pre/postsynaptic unit had to be maintained strictly to observe postsynaptic downregulation. Using a highly potent and stereospecific inhibitor of cyclic AMP hydrolysis we demonstrate that downregulation can also be elicited by postsynaptic mechanisms. Treatment of rats with rolipram, a phenylpyrrolidinone derivative, decreases adrenoceptor density in a time- and dose-dependent fashion. The ED50 for the racemate is 0.35 mg/kg, for the (-)-isomer 0.18 mg/kg. The (+)-isomer is inactive. This effect correlates with the drug's potency to inhibit a calmodulin/calcium-insensitive phosphodiesterase from brain cortex (ED50 racemate: 1.2 microM; (-)-isomer: 0.4 microM). Using methods of computer-assisted drug design to identify common stereochemical features of rolipram and the unrelated tricyclic antidepressants, we found that calculated low energy conformations fit onto a four-point model which specifies four hypothetical binding sites between a drug and its presumptive receptor site. These findings may indicate that all antidepressants share a common, hitherto unknown site of action irrespective of their known biochemical activities.