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 pituitay dopamine receptors responsible for prolactin inhibition are outside the blood brain barrier. This project therefore 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 the blood brain barrier. During the first year of this project we synthesized a series of benzoquinolines as dopamine agonists lacking the ergot indole moiety. The dihydroxy compounds in the Beta-rotameric configuration (hydroxy groups in the 8,9 positions) were shown to be potent dopamine agonists by their ability to suppress prolactin (PRL) secretion in cultured anterior pituitary cells. These agents also displaced 3H-spiperone bound to anterior pituitary dopamine receptors in a biphasic fashion as observed for most dopamine agonists. During the second year of the proposal we will examine the ability of these agents to cross the blood brain barrier by their capacity to stimulate dihydroxyphenylacetic acid (DOPAC) formation in the caudate nucleus. The duration of action of the agents will be tested by their ability to suppress PRL secretion in vivo in MBH lesioned rats. During the renewal period additional compounds will be synthesized in which the 2-substituent will be varied to influence the lipophilicity and polarity of the compounds, and to maximize potency by improvng the steric interaction of the agonist with the receptor, with the goal of obtaining a potent but highly polar molecule which will not cross the blood brain barrier. The overall hydrophobicity of the agents will be monitored by determining their octanol/water partition coefficients. The new compounds will be tested in radio ligand binding assays, by their capacity to suppress PRL secretion, for their ability to cross the blood brain barrier, and for their duration of action.
| 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 |
