title: Further in vitro and in vivo studies with the putative presynaptic dopamine agonist N,N-dipropyl-7-hydroxy-2-aminotetralin.
abstract: The in vitro binding of the putative dopamine autoreceptor agonist [3H]DP-7-ATN to rat striatal membrane homogenates was investigated. The maximum number of binding sites Bmax was 497.5 +/- 50.2 fmol/mg protein and the affinity constant KD was 8.3 +/- 1.5 nM using 10 microM (+) butaclamol to define non-specific binding. Lesion of the left medium forebrain bundle by 6-hydroxydopamine resulted in an almost complete loss of dopamine in the striatum but did not affect the binding of [3H]DP-7-ATN. The binding of [3H]DP-7-ATN to the homogenates of the dopaminergic cell bodies in the substantia nigra revealed a Bmax of 542.4 +/- 40.1 fmol/mg protein and a KD of 11.1 +/- 1.3 nM. The pharmacological profile of the binding was characterized as being to D-2 receptors. No direct in vitro evidence could be found for a selective binding to DA autoreceptors. The dopamine uptake inhibitor GBR 12909 interacted in a noncompetitive manner with the in vitro binding of [3H]DP-7-ATN and the latter compounds uptake into isolated synaptosomes was not through the specific dopamine uptake system but rather through diffusion. GBR 12909 failed to reveal any agonistic or antagonistic activity in the GBL model but was able to antagonize the hypomotility in rats induced by 0.25 mg/kg DP-7-ATN. The inhibitory effect of DP-7-ATN on DA release was also demonstrated using in vivo brain dialysis in conscious rats. Based on the above results, the possibility is discussed that the release regulating DA autoreceptors, which might be coupled to the reuptake complex, and the DA biosynthesis regulating autoreceptors, are different entities.
authors.affiliation: Department of Medicinal Chemistry, State University Groningen, The Netherlands.
authors.forename: T B
authors.initials: TB
authors.lastname: Mulder
authors.forename: J B
authors.initials: JB
authors.lastname: de Vries
authors.forename: D
authors.initials: D
authors.lastname: Dijkstra
authors.forename: J W
authors.initials: JW
authors.lastname: Wiechers
authors.forename: C J
authors.initials: CJ
authors.lastname: Grol
authors.forename: A S
authors.initials: AS
authors.lastname: Horn
mesh_terms: D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000378:metabolism; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D009281:Naphthalenes; D010879:Piperazines; D011954:Receptors, Dopamine; D017981:Receptors, Neurotransmitter; D013764:Tetrahydronaphthalenes; D013134:Spiperone; C043425:vanoxerine; D001058:Apomorphine; D015107:4-Butyrolactone; C031349:7-hydroxy-2-N,N-dipropylaminotetralin; D004298:Dopamine