Pharmacological profile of N,N dipropyl-8-hydroxy-3-chromanamine, an oxygen isostere of the dopamine agonist N,N dipropyl-5-hydroxy-2-aminotetralin with enhanced presynaptic selectivity.
The pharmacological profile of N,N dipropyl-8-hydroxy-3-chromanamine (DP-8OH-3CA), the oxygen isostere of N,N dipropyl-5-hydroxy-2-aminotetralin (DP-5OH-AT), was studied and the results compared to its carbon analogue and apomorphine. The chromanamine was found to displace the D2-dopaminergic ligand [3H] 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin with a higher potency than apomorphine and DP-5OH-AT; the IC50 values were 8, 11 and 16 nM, respectively. Experiments investigating the effects of these compounds on dopamine metabolism following oral (o.a.) and intraperitoneal administration (i.p.) showed that the chromanamine had an excellent o.a./i.p. ratio. The presynaptic actions on D2-dopamine receptors, which were studied using tyrosine hydroxylase inhibition, modulation of dopamine metabolism, prevention of alpha-methyl-p-tyrosine induced dopamine depletion in rats and hypomotility in mice, showed that the chromanamine acts as a D2-agonist with half maximal effects between 0.1 and 0.4 mumol/kg (i.p.) DP-8OH-3CA was found to evoke obvious postsynaptic effects when studied in such models as stereotyped behaviour, hyperlocomotion, turning behaviour in 6 hydroxydopamine lesioned rats and reserpine reversal. Stereotypy and the accompanying hyperlocomotion were found to be induced at a half maximal dose of 17 mumol/kg (i.p.). Both with the stereotyped and turning behaviours, a long duration of action was evident. The selectivity for presynaptic receptors was found to be 6.7 times higher than that of DP-5OH-AT, indicating that oxygen substitution can cause an enhancement of selectivity for presynaptic D2-dopamine receptors. Experiments on noradrenaline release and on serotonin synthesis showed that DP-8OH-3CA had only moderate affinity for 5-hydroxytryptamine and noradrenaline receptors. It is concluded that DP-8OH-3CA is a potent D2-agonist with an excellent o.a./i.p. ratio and enhanced selectivity for presynaptic dopamine receptors.
Department of Medicinal Chemistry, Faculty of Pharmacy, University of Groningen, The Netherlands.
N A
NA
Vermue
B
B
Kaptein
P G
PG
Tepper
J B
JB
de Vries
A S
AS
Horn
D015107:4-Butyrolactone / Q000037:antagonists & inhibitors; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D002839:Chromans; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D013569:Synapses / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D001578:Benzopyrans; D002839:Chromans; D009281:Naphthalenes; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; C055144:8-hydroxy-3,4-dihydro-3-(dipropylamino)-2H-1-benzopyran; D012701:Serotonin; C031457:DK 118; D015107:4-Butyrolactone; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid