Presynaptic inhibition of dopamine synthesis in rat striatal tissue by enantiomeric mono- and dihydroxyaporphines.
Presynaptic autoreceptor-mediated modulation of dopamine (DA) synthesis was evaluated as the inhibition of tyrosine hydroxylase activity by enantiomeric mono- and dihydroxyaporphines with minced striatal tissue from rat brain. The isomers of N-n-propylnorapomorphine (NPA) both inhibited tyrosine hydroxylase activity [IC50 = 0.3 and 1.0 microM for (R)-(-)- and (S)-(+)-NPA, respectively; R/S potency = 3.6]. Their effects were fully blocked by the nonselective DA receptor antagonist fluphenazine, as well as by the D2-selective antagonist spiperone, but not by the D1 antagonist SCH-23390. These results suggest a D2-type autoreceptor-mediated inhibition of DA synthesis, with limited enantiomeric selectivity of this catechol-aporphine. The corresponding monohydroxy analogs, (R)-(-)- and (S)-(+)-11-hydroxy-N-n-propylnoraporphine (11-OH-NPa) were about 100 times less potent (IC50 = 42 and 87 microM, respectively) than the NPA isomers in fully inhibiting the enzyme activity in normal tissue but, after depletion of endogenous DA by acute in vivo pretreatment with reserpine (which did not alter the number of D1 or D2 specific binding sites), (R)-(-)-11-OH-NPa was a highly potent but partial agonist (IC25 = 7 nM). Fluphenazine and spiperone fully antagonized the inhibition of tyrosine hydroxylase by (R)-(-)-11-OH-NPa in reserpinized tissue, but SCH-23390 was ineffective. Actions mediated by endogenous DA probably contribute to the effect of high concentrations of (R)-(-)-11-Oh-NPa to evoke a full inhibition of DA synthesis, but its high potency partial agonist effects appear to be mediated by D2-autoreceptors. (S)-(+)-11-OH-NPa was a very weak partial agonist in reserpinized tissue, with an IC25 = 30 microM (essentially the same as normal tissue); thus, (R)-(-)-11-OH-NPa was greater than 4,000 times more potent than its S-(+)-enantiomer in the absence of endogenous DA. These results demonstrate that NPA, which contains a catechol moiety, acts as a full agonist to inhibit striatal DA synthesis via a presynaptic autoreceptor of the D2 type, with only slight stereoselectivity, and that its monohydroxy analog is a very potent but partial D2 autoreceptor agonist, with very high stereoselectivity.
Booth
R G
RG
Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02114.
Baldessarini
R J
RJ
Kula
N S
NS
Gao
Y
Y
Zong
R
R
Neumeyer
J L
JL
D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001060:Aporphines / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012110:Reserpine / Q000494:pharmacology; D013237:Stereoisomerism; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors
D001060:Aporphines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C009074:N-n-propylnorapomorphine; D012110:Reserpine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D004298:Dopamine