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

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 (5a-e and 6a-e) were synthesi zed as conformationally rigid analogues of 1-benzyltetrahydroisoquinoline a nd evaluated for their affinity at D-1 and D-2 dopamine receptors. All comp ounds showed lower D1 and D affinities than dopamine. The 5-hydroxy-1-methy l-2,3,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij] 5a and the 5,6dihydrox y analogue 6a showed D-2 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 t he distances from meta and para hydroxyl oxygens to the nitrogen and the he ight of nitrogen from the hydroxylated phenyl ring plane) of the dopaminerg ic pharmacophore embedded in our compounds have lower values in comparison with those observed in D-1 and D-2 selective ligands. (C) 2001 Elsevier Sci ence Ltd. All rights reserved.