Binding and preliminary evaluation of 5-hydroxy- and 10-hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines as dopamine receptor ligands

Citation
F. Claudi et al., Binding and preliminary evaluation of 5-hydroxy- and 10-hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines as dopamine receptor ligands, J MED CHEM, 43(4), 2000, pp. 599-608
Citations number
26
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
43
Issue
4
Year of publication
2000
Pages
599 - 608
Database
ISI
SICI code
0022-2623(20000224)43:4<599:BAPEO5>2.0.ZU;2-T
Abstract
The N-methyl, N-ethyl, and N-n-propyl derivatives of 5-hydoxy- and 10-hydro xy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines were were prepared as monophenolic ligands for the dopamine receptor and evaluated f or their affinity at D-1-like and D-2-like subtypes. All compounds showed v ery low D-1 affinities. This could be ascribed to the absence of a catechol nucleus or of the beta-phenyldopamine pharmacophore. Only the N-methyl-5-h ydroxy- (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 t he D-2 receptors with low affinity, in the same range as dopamine. In compo unds 5a and so, the 2-(3-hydroxyphenyl)ethylamine moiety does not meet the requirements of the D-2 agonist pharmacophore: namely, the 2-(3-hydroxyphen yl)ethylamine does not reach the trans, fully extended conformation. The th ree compounds did not interact with recombinant human D-4 receptors, and on ly 5a showed low affinity for rat recombinant D-3 receptors. Analysis of th e influence of Na+ on [H-3]spiperone binding showed that 5a displays a pote ntial dopamine D-2 agonist profile, whereas 6a probably has a dopamine D-2 antagonist activity. The D-2 agonist activity of 5a was proved by the effec ts on prolactin release from primary cultures of rat anterior pituitary cel ls.