title: Neuropharmacological profile of a new series of dopamine agonists: N-n-propyl-hexahydronaphthoxazines.
abstract: 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.
mesh_terms: D015107:4-Butyrolactone / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003000:Clonidine / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D010078:Oxazines / Q000494:pharmacology*; D011224:Prazosin / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D009281:Naphthalenes; D010078:Oxazines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012110:Reserpine; D003000:Clonidine; D015107:4-Butyrolactone; D011224:Prazosin