N-0437: a selective D-2 dopamine receptor agonist in in vitro and in vivo models

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.