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

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 were prepared as monophenolic ligands for the dopamine receptor and evaluated for their affinity at D-1-like and D-2-like subtypes. All compounds showed very 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-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 D-2 receptors with low affinity, in the same range as dopamine. In compounds 5a and so, the 2-(3-hydroxyphenyl)ethylamine moiety does not meet the requirements of the D-2 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 D-4 receptors, and only 5a showed low affinity for rat recombinant D-3 receptors. Analysis of the influence of Na+ on [H-3]spiperone binding showed that 5a displays a potential 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 effects on prolactin release from primary cultures of rat anterior pituitary cells.