Neurochemical and behavioral evidence that Ro 41-9067 is a selective presynaptic dopamine receptor agonist.
(-)-2,3,4a,5,6,10b-Hexahydro-7-hydroxy-2-methylbenzo(f)-quinoline 4(1H)-ethanol (Ro 41-9067) was compared with apomorphine, 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine (B-HT 920), lisuride and other dopamine (DA) receptor agonists in a series of tests designed to characterize its pharmacological activity on DA receptors. In vitro binding studies indicated that Ro 41-9067 bound selectively to DA D2 vs. D1 receptors. It also had a moderate affinity for serotonin1A and alpha-2 adrenergic receptors. Ro 41-9067 exhibited a marked agonistic component for the presynaptic DA autoreceptors. Indeed, it caused a dose-related reduction in locomotor activity over a wide dose range and prolonged periods of observation without stimulating locomotor activity, reflecting postsynaptic DA receptor activation, even at the highest doses. Ro 41-9067 inhibited the gamma-butyrolactone-induced increase in I-dopa accumulation in the rat striatum, an effect sensitive to haloperiodol. Ro 41-9067 inhibited K(+)-induced [3H]DA release and significantly reduced the striatal contents of the DA metabolites, dihydroxyphenilacetic acid and homovanillic acid. Furthermore, the compound counteracted stereotyped behavior and locomotor stimulation induced by amphetamine. Finally, Ro 41-9067 did not appear to act on postsynaptic D2 receptors because it, similarly to B-HT 920 but differently from bromocriptine, quinpirole and lisuride, did not change basal or forskolin-stimulated adenylate cyclase activity. Only at very high concentrations Ro 41-9067 increased adenylate cyclase activity, this effect being due to a D1 agonistic component.(ABSTRACT TRUNCATED AT 250 WORDS)
Nisoli
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E
Department of Biomedical Sciences and Biotechnologies, University of Brescia, Italy.
Tonello
C
C
Imhof
R
R
Scherschlicht
R
R
da Prada
M
M
Carruba
M O
MO
D015107:4-Butyrolactone / Q000037:antagonists & inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000661:Amphetamine / Q000037:antagonists & inhibitors; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002375:Catalepsy / Q000139:chemically induced; D003342:Corpus Striatum / Q000033:anatomy & histology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007980:Levodopa / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010477:Perfusion; D011188:Potassium / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors; D014316:Tritium
D015306:Biogenic Monoamines; D015259:Dopamine Agents; D011804:Quinolines; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; D014316:Tritium; C082216:Ro 41-9067; D007980:Levodopa; D000661:Amphetamine; D000262:Adenylyl Cyclases; D001058:Apomorphine; D015107:4-Butyrolactone; D011188:Potassium; D004298:Dopamine