Although several ergot derivatives have been effective in reducing both the volume of pituitary tumors and the serum prolactin level in hyperprolactinemia, the use of these drugs is often accompanied by undesirable side effects. These effects are possibly due to the presence of the intact ergot structure in the drug molecules or to actions at dopamine receptors within the central nervous system. Anterior pituitary dopamine receptors responsible for prolactin inhibition are outside the blood brain barrier. This project proposes the synthesis of more specific dopamine agonists (modified to mimic the conformation of dopamine at the receptor, but lacking the ergot indole moiety). Hydrophilic groups will be added in an attempt to produce compounds which only act outside of the blood brain barrier. New agents will be characterized by their ability to compete for 3H-spiperone or 3H-domperidone bound to membrane preparations of the anterior pituitary. Two such compounds have been synthesized to test our hypothesis. The first has been found to be equipotent with dopamine in competing for 3H-domperidone binding, with an IC50 of 100 nM, while the second is more than ten times as active, with an IC50 of 10 nM. Binding potencies will be compared to the ability of agents to suppress prolactin secretion from cultured anterior pituitary cells. The ability of compounds to cross the blood brain barrier will be determined by comparing their effects on rotational behavior following either intravenous or intraventricular administration. Dopamine receptors involved in rotational behavior lie within the blood brain barrier.
| Craig, J C; Torkelson, S M; Findell, P R et al. (1989) Synthesis and dopaminergic activity of 2-substituted octahydrobenzo[f]quinolines. J Med Chem 32:961-8 |
| Findell, P R; Torkelson, S M; Craig, J C et al. (1988) Correlation of alpha- and beta-rotameric forms of 2-substituted octahydrobenzo[f]quinoline dopamine congeners with high and low affinity states of the anterior pituitary dopamine receptor and prolactin inhibition. Mol Pharmacol 33:78-83 |
