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
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
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.