| Popis: |
We have synthesized several 3-amino-6-phenyl pyridazines in which the amino substituent is a linear butyrophenone moiety (compounds 8 and 10), a cyclic butyrophenone moiety (compound 3), or a phenylpiperazine fragment (compound 2). Compound 8 potently inhibited [3H]spiperone binding to striatal D2 receptors and [3H]SCH 23390 binding to striatal D1 receptors (Ki in the nanomolar range but lower than that of haloperidol). Compounds 3, 2 and 10 showed no affinity for dopamine (DA) receptors. Only 2 compounds (3 and 8) inhibited [3H]ketanserin binding to cortical 5-HT2A receptors; compound 8 strongly inhibited binding with a Ki similar to that of methysergide, while binding was only weakly inhibited by compound 3. The DA and 5-HT2A antagonist activity of compound 8 was evaluated in vivo and in vitro. The results in standard screening tests indicate that this compound possesses neuroleptic activity. However, in contrast to haloperidol, compound 8 did not modify DA and its metabolite levels in rat striatum, or induce catalepsy. It inhibited serotonin-induced contractions in endothelium-stripped aorta with a pA2 of 8.26 and did not affect reserpine-induced palpebral ptosis, indicating that it does not have antidepressant activity; compound 10, however, showed slight activity in this test. |
