Enantiomers of monohydroxy-2-aminotetralin derivatives and their activity at dopamine autoreceptors as studied by brain dialysis.
The enantiomers of a series of dopamine (DA) agonists, monohydroxy-2-aminotetralin derivatives, were investigated using brain microdialysis. We used a 5-OH-substituted derivative, N-0437 (2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin), and three 7-OH-substituted derivatives, N-0438 (2-(N-propyl-N-2-thienylethylamino)-7-hydroxytetralin), 7-OH-DPAT (7-hydroxy-2-(N,N-di-n-propylamino)tetralin) and PHNO (4-propyl-9-hydroxynaphthoxazine; position 9 of the naphtoxazines corresponds to position 7 of the aminotetralins). We studied the activity of the enantiomers at autoreceptors regulating the release of DA following their local infusion into the striatum of the rat. We were particularly interested in the activity of R(+)-N-0437, S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, which are enantiomers that have been classified as less potent or inactive in previous studies. S(-)-N-0437, R(+)-N-0438, R(+)-7-OH-DPAT and R(+)-PHNO decreased DA release by 45-60%. Thus, these enantiomers are potent agonists at autoreceptors regulating the release of DA. The R(+) enantiomer of the 5-OH-substituted derivative N-0437 possessed antagonistic activity at autoreceptors controlling DA release, increasing DA release by 100%. This finding is consistent with reports showing that one enantiomer of other 5-OH DA agonists displays agonistic activity, while the other has antagonistic properties at DA autoreceptors. The less potent enantiomers of the 7-OH-substituted derivatives S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, however, all showed weak agonistic activity at DA autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Timmerman
W
W
Department of Medicinal Chemistry, University Centre of Pharmacy, Groningen, The Netherlands.
Tepper
P G
PG
Dijkstra
D
D
Stoelwinder
H
H
Grol
C J
CJ
Westerink
B H
BH
Horn
A S
AS
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D008297:Male; D010078:Oxazines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D013223:Statistics as Topic; D013237:Stereoisomerism; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology
D015259:Dopamine Agents; D010078:Oxazines; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C042631:naxagolide; C047508:rotigotine; D004298:Dopamine