title: N-0437: a selective D-2 dopamine receptor agonist in in vitro and in vivo models.
abstract: The selectivity of the potent dopamine D-2 agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) was examined in a series of in vivo and in vitro pharmacological models. In radioligand binding assays, N-0437 showed high potency (Ki = 0.69 nM) and selectivity for D-2 receptors as compared to its potency and selectivity at various other neuronal receptors (Ki in nM): D-1 (678) dopamine, alpha 1-(534) and alpha 2-(195) adrenoceptor, S1-(6940) and S2-(5900) serotonin and muscarine (2660). Very low activity (Ki greater than 10(-5) M) was seen at the beta-adrenoceptor, A1-adenosine, GABAA and benzodiazepine receptors. Furthermore, N-0437 inhibited the calcium-dependent release of [3H]dopamine (IC50: 4 nM) and [3H]acetylcholine (IC50: 6.3 nM) from rabbit striatal slices in the nanomolar range. These effects of N-0437 were mediated through activation of D-2 dopamine autoreceptors and D-2 dopamine heteroreceptors, respectively. Presynaptic dopaminergic activity in vivo was measurable as an inhibition of the locomotor activity of mice, and in this model N-0437 was more effective than apomorphine. Moreover, the effect of N-0437 could be antagonized by sulpiride but not by yohimbine. N-0437 was equipotent with apomorphine in inducing circling behaviour in 6-OHDA-lesioned rats. N-0437 had almost no serotonergic activity in vivo. The results show that N-0437 is a selective dopamine D-2 agonist, and thus, that it is a new ligand of choice for studies on the D-2 receptor.
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004558:Electric Stimulation; D006892:Hydroxydopamines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D016627:Oxidopamine; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D012701:Serotonin / Q000096:biosynthesis; D013239:Stereotyped Behavior / Q000187:drug effects; D013563:Sympathectomy, Chemical; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D006892:Hydroxydopamines; D009281:Naphthalenes; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D012701:Serotonin; C047508:rotigotine; D016627:Oxidopamine; D000109:Acetylcholine; D002118:Calcium; D004298:Dopamine