1.
Denbufylline has been examined for its ability to inhibit
cyclic nucleotide phosphodiesterase isoenzymes from rat cardiac ventricle and cerebrum, as well as for its affinity for
adenosine A1 and A2 receptors and the re-uptake site. For comparison,
SK&F 94120,
theophylline and 3-isobutyl-1-methyl-xanthine (
IBMX) were examined as
phosphodiesterase inhibitors whilst
N6-cyclohexyladenosine, R(-)-N6-(2-phenylisopropyl)-adenosine, 5'-N-ethylcarboxamido-adenosine, 2-nitrobenzylthioinosine,
theophylline and
IBMX were examined for their affinity for
adenosine binding sites. 2. This investigation confirmed the presence of four
phosphodiesterase activities in rat cardiac ventricle; in rat cerebrum only three were present. 3.
Denbufylline selective inhibited one form of Ca2+-independent, low Km
cyclic AMP phosphodiesterase. The form inhibited was one of two present in cardiac ventricle and the sole one in cerebrum. This form was not inhibited by
cyclic GMP. The inotropic agent
SK&F 94120 selectively inhibited the form of
cyclic AMP phosphodiesterase which was inhibited by
cyclic GMP present in cardiac ventricle.
Theophylline and
IBMX were relatively non-selective
phosphodiesterase inhibitors. 4.
Denbufylline was a less potent inhibitor of
ligand binding to
adenosine receptors than of
cyclic AMP phosphodiesterase. This contrasted with
theophylline, which had a higher affinity for
adenosine receptors, and
IBMX which showed no marked selectivity.
Denbufylline,
theophylline and
IBMX all had a low affinity for the
adenosine re-uptake site. 5.
Denbufylline is being developed as an agent for the
therapy of
multi-infarct dementia. The selective inhibition of a particular low Km
cyclic AMP phosphodiesterase may account for the activity of this compound.