Van der Weide J, Tendijck M E, Tepper P G, De Vries J B, Dubocovich M L, Horn A S
Department of Medicinal Chemistry, State University of Groningen, The Netherlands.
Eur J Pharmacol. 1988 Feb 9;146(2-3):319-26. doi: 10.1016/0014-2999(88)90309-3.
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.
