It has been demonstrated that within the series of hydroxylated (7-OH, 9-OH) and non-hydroxylated (N-0498) hexahydronaphthoxazines the 9-OH (N-0500) analogue is a very potent centrally acting DA receptor agonist. In in vitro [3H]DP-5,6-
ADTN binding experiments, reflecting D-2 dopaminergic activity,
N-0500 was equipotent with
apomorphine and
RU-29717, whereas both the 7-OH (N-0499) and N-0498 were much less effective. In in vivo tests related to DA receptor stimulation
N-0500 was found to be the most active compound. In the
gamma-butyrolactone model, a test for DA
autoreceptor activation,
N-0500 was 10 times as potent as
apomorphine, but 3 times less active than
RU-29717. The locomotor activity of mice was inhibited more strongly by
N-0500 than by
N-0499. Striatal concentrations of
3,4-dihydroxyphenylacetic acid and
homovanillic acid were rapidly reduced by
N-0500 both after intraperitoneal and
oral administration, indicating that this compound is well absorbed from the gastrointestinal tract and passes the blood-brain barrier to activate DA
autoreceptors. In models for postsynaptic DA receptor stimulation (induction of stereotypy in rats, reversal of
reserpine-induced immobility of mice)
N-0500 was found to be as effective as
RU-29717 in inducing stereotyped behaviors in rats, but was much less effective than
RU-29717 in restoring the mobility of reserpinized mice, suggesting a selectivity for D-2 DA receptors by
N-0500 in contrast to the mixed D-1/D-2 receptor activity of
RU-29717. In in vitro binding experiments for evaluating the affinity towards other receptor types,
N-0500 exhibited only a weak affinity towards 5-HT1 and alpha 2 binding sites and possessed a very weak affinity for 5-HT2 and alpha 1 receptor sites. It was concluded from these in vitro binding experiments that
N-0500, has not only a very high affinity for D-2 DA receptors, but is more selective than
RU-29717 and much more selective than the ergot
bromocriptine. On the basis of its very potent in vivo central D-2
dopamine receptor activities and its in vitro selectivity,
N-0500, being the most potent compound within the series, is a much more specifically acting
drug than many of the dopaminergic
ergolines and might therefore be a good candidate for the treatment of
Parkinson's disease.