title: Biochemical and functional studies on EMD 49,980: a potent, selectively presynaptic D-2 dopamine agonist with actions on serotonin systems.
abstract: EMD 49,980 proved to be a potent and selectively presynaptic D-2 dopamine receptor agonist in biochemical studies with rats. Thus, the gamma-butyrolactone-induced accumulation of dihydroxyphenylalanine, used as a presynaptic model, was antagonized with ED50 values of 0.29 and 0.09 mumol/kg in striatum and t. olfactorium, respectively, with high maximal effects. In contrast, striatal acetylcholine concentrations, reflecting actions at normosensitive postsynaptic D-2 receptors, were only moderately increased by about 30% over a dose range of 2.3-68 mumol/kg. In rats with unilateral nigrostriatal lesions, EMD 49,980 induced long-lasting contralateral turning, indicative of agonistic actions at denervated postsynaptic D-2 receptors. In addition, EMD 49,980 potently inhibited serotonin (5-HT) uptake in vitro and in vivo. Binding studies confirmed D-2 activity in the nM range but, similarly potent effects were observed at 5-HT1A binding sites. Measurement of 5-hydroxytryptophan (5-HTP) accumulation in the n. raphe revealed that, in vivo, the net effect of EMD 49,980 on 5-HT systems is an agonistic one. Control experiments indicate that inhibition of 5-HTP accumulation by EMD 49,980 is induced mainly via direct activation of 5-HT1A receptors, although some contribution due to 5-HT uptake inhibition is likely. Furthermore, results with various reference compounds make it unlikely that there are indirect effects, also via alpha 2-receptors in the models used and support the view that D-2 agonistic, 5-HT uptake inhibiting and 5-HT1A agonistic actions are independent properties of EMD 49,980.
authors.affiliation: Department of Neurochemistry, E. Merck, Darmstadt, F.R.G.
authors.forename: C A
authors.initials: CA
authors.lastname: Seyfried
authors.forename: H E
authors.initials: HE
authors.lastname: Greiner
authors.forename: A F
authors.initials: AF
authors.lastname: Haase
mesh_terms: D015107:4-Butyrolactone / Q000494:pharmacology; D006916:5-Hydroxytryptophan / Q000378:metabolism / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006892:Hydroxydopamines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D016627:Oxidopamine; D000078183:Oxindoles; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D010133:p-Chloroamphetamine / Q000037:antagonists & inhibitors
chemical_list: D015259:Dopamine Agents; D006892:Hydroxydopamines; D007211:Indoles; D000078183:Oxindoles; D011725:Pyridines; D012701:Serotonin; C059613:roxindole; D004295:Dihydroxyphenylalanine; D010133:p-Chloroamphetamine; D012110:Reserpine; D016627:Oxidopamine; D006916:5-Hydroxytryptophan; D000109:Acetylcholine; D015107:4-Butyrolactone