Synthesis and preliminary pharmacological evaluation of 5-Hydroxy- and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline derivatives as dopamine receptor ligands

详细信息    查看全文

• 作者：Cingolani ; Gian Mario ; Di Stefano ; Antonio ; Napolitani ; Fabrizio ; Mosciatti ; Barbara ; Giorgioni ; Gianfabio ; et. al.
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2001
• 出版时间：June, 2001
• 年：2001
• 卷：9
• 期：6
• 页码：1447-1458
• 全文大小：608 K

文摘

A series of 5-hydroxy- and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline derivatives were synthesized as conformationally rigid analogues of 1-benzyltetrahydroisoquinoline and evaluated for their affinity at D₁ and D₂ dopamine receptors. All compounds showed lower D₁ and D₂ affinities than dopamine. The 5-hydroxy-1-methyl-2,3,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline and the 5,6-dihydroxy analogue showed D₂ agonist activity. This was proved by their effects on prolactin release from primary cultures of rat anterior pituitary cells. Molecular modeling studies showed that the geometric parameters (namely the distances from meta and para hydroxyl oxygens to the nitrogen and the height of nitrogen from the hydroxylated phenyl ring plane) of the dopaminergic pharmacophore embedded in our compounds have lower values in comparison with those observed in D₁ and D₂ selective ligands.