Binding and Preliminary Evaluation of 5-Hydroxy- and 10-Hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-i j]isoquinolines as Dopamine Receptor Ligands

The N-methyl, N-ethyl, and N-n-propyl derivatives of 5-hydoxy- and 10-hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines were prepared as monophenolic ligands for the dopamine receptor and evaluated for their affinity at D1-like and D2-like subtypes. All compounds showed very low...

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Veröffentlicht in:Journal of medicinal chemistry 2000-02, Vol.43 (4), p.599-608
Hauptverfasser: Claudi, Francesco, Di Stefano, Antonio, Napolitani, Fabrizio, Cingolani, Gian Mario, Giorgioni, Gianfabio, Fontenla, Josè A, Montenegro, Gisela Y, Rivas, Maria E, Rosa, Elizabeth, Michelotto, Barbara, Orlando, Giustino, Brunetti, Luigi
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Sprache:eng
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Zusammenfassung:The N-methyl, N-ethyl, and N-n-propyl derivatives of 5-hydoxy- and 10-hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines were prepared as monophenolic ligands for the dopamine receptor and evaluated for their affinity at D1-like and D2-like subtypes. All compounds showed very low D1 affinities. This could be ascribed to the absence of a catechol nucleus or of the β-phenyldopamine pharmacophore. Only the N-methyl-5-hydroxy- (5a), N-methyl-10-hydroxy- (6a), and N-methyl-4-bromo-10-methoxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines (26a) bound the D2 receptors with low affinity, in the same range as dopamine. In compounds 5a and 6a, the 2-(3-hydroxyphenyl)ethylamine moiety does not meet the requirements of the D2 agonist pharmacophore:  namely, the 2-(3-hydroxyphenyl)ethylamine does not reach the trans, fully extended conformation. The three compounds did not interact with recombinant human D4 receptors, and only 5a showed low affinity for rat recombinant D3 receptors. Analysis of the influence of Na+ on [3H]spiperone binding showed that 5a displays a potential dopamine D2 agonist profile, whereas 6a probably has a dopamine D2 antagonist activity. The D2 agonist activity of 5a was proved by the effects on prolactin release from primary cultures of rat anterior pituitary cells.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm991034o