title: The enantiomers of the D-2 dopamine receptor agonist N-0437 discriminate between pre- and postsynaptic dopamine receptors.
abstract: The (+) and (-) enantiomers of the substituted 2-aminotetralin, N-0437 were evaluated in vivo for their dopaminergic activity, using biochemical as well as behavioural models. In presynaptic models, i.e. antagonism of gamma-butyrolactone-induced dihydroxyphenylalanine elevations and the induction of hypomotility, both enantiomers exhibited a similar high degree of potency. Following postsynaptic stimulation, (-)N-0437 was able to induce stereotypy in rats in a dose-dependent manner. Moreover this compound was able to produce rotation in 6-hydroxy-dopamine-lesioned rats. In contrast, at the doses tested (i.e. 1 and 10 mumol/kg, i.p.), (+)N-0437 displayed virtually no activity at all in either of these postsynaptic models. From in vitro evoked release studies of [3H]acetylcholine it became clear that (-)N-0437 is a postsynaptic dopamine agonist, while (+)N-0437 is a weak antagonist at these receptors. Taken together, the results indicate that (-)N-0437 is very selective for the stimulation of postsynaptic dopamine receptors, while (+)N-0437 stimulates presynaptic dopamine receptors and blocks postsynaptic receptors. These properties make (+)- and (-)N-0437 very promising candidates for psychotherapeutic use.
authors.affiliation: Department of Medicinal Chemistry, State University of Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Van der Weide
authors.forename: M E
authors.initials: ME
authors.lastname: Tendijck
authors.forename: P G
authors.initials: PG
authors.lastname: Tepper
authors.forename: J B
authors.initials: JB
authors.lastname: De Vries
authors.forename: M L
authors.initials: ML
authors.lastname: Dubocovich
authors.forename: A S
authors.initials: AS
authors.lastname: Horn
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D017448:Receptors, Dopamine D2; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D009281:Naphthalenes; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D017981:Receptors, Neurotransmitter; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine; D000109:Acetylcholine; D004298:Dopamine