The enantiomers of the dopamine agonist N-0437: in vivo and in vitro effects on the release of striatal dopamine.
The enantiomers of the potent and selective dopamine (DA) D-2 receptor agonist 2-(N-propyl-N-2-thienylethyl-amino)-5-hydroxytetralin, N-0437, were tested for their pharmacological actions on DA D-2 autoreceptors in vivo, by measuring DA release by microdialysis during local administration of both drugs and in vitro, by measuring their effects on the electrically stimulated release of [3H]DA from striatal slices. In both experimental situations (-)-N-0437, at low doses, acted as an agonist on receptors controlling DA release. However, in vivo at a concentration of 10 microM (-)-N-0437 induced a short-lasting increase in DA release and in vitro the inhibitory effect of (-)-N-0437 was significantly less pronounced at higher concentrations (1-10 microM). (+)-N-0437 (0.1-10 microM) showed an antagonistic action both in vivo and in vitro. Following inhibition of the neuronal impulse flow with tetrodotoxin, (+)-N-0437 failed to increase DA release suggesting the effect of this enantiomer is not associated with an amphetamine-like action on the nerve terminal. The use of the DA re-uptake inhibitor GBR 12909 confirmed the antagonism of (+)-N-0437 towards DA receptors. Since it is known that (+)-N-0437 acts as an agonist on DA D-2 autoreceptors controlling the synthesis of DA, these results provide additional evidence for the existence of distinct DA D-2 autoreceptor populations involved in the release and synthesis of DA. The differential actions of (-)- and (+)-N-0437 gave rise to mutual antagonism of the actions of the enantiomers both in vivo and in vitro, thus providing a strong argument for using the enantiomers instead of the racemate in clinical situations.
Timmerman
W
W
Department of Pharmacy, State University of Groningen, The Netherlands.
Dubocovich
M L
ML
Westerink
B H
BH
De Vries
J B
JB
Tepper
P G
PG
Horn
A S
AS
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D002404:Catheterization; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D004558:Electric Stimulation; D007608:Kainic Acid; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D013997:Time Factors
D015259:Dopamine Agents; D009281:Naphthalenes; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D013779:Tetrodotoxin; C047508:rotigotine; C043425:vanoxerine; D001058:Apomorphine; D007608:Kainic Acid; D004298:Dopamine