Abstract
The interaction of the enantiomers of the novel dopamine agonist, 3-PPP (3-(3-hydroxyphenyl)-N-n-piperidine) with the dopamine receptor in the anterior pituitary gland was examined. Both (+)- and (-)-3-PPP were effective in suppressing the elevation in serum prolactin (PRL) concentrations in rats treated with α-methyl-paratyrosine, an inhibitor of dopamine synthesis. The (+)-enantiomer was slightly more potent than the (-)-enantiomer in this regard. In addition, the secretion of PRL from anterior pituitary tissue under in vitro conditions was significantly inhibited by both isomers of 3-PPP, with (+)-3-PPP being approximately 10 times more potent than (-)-3-PPP. Both (+)- and (-)-3-PPP displaced 3H-(-)-N-n-propylnorapomorphine (3H-NPA) and 3H-spiperone from bovine anterior pituitary membranes. The Hill coefficients of (+)- and (-)-3-PPP for the displacement of 3H-spiperone were 0.6 and 0.7, respectively. These results are consistent with the view that the (+)- and (-)-enantiomer exhibit dopamine agonist effects at dopamine receptor sites in the anterior pituitary gland. However, (+)-3-PPP demonstrated marked differences in affinity for 3H-NPA- and 3H-spiperone labeled-sites, whereas (-)-)3-PPP showed the same order of affinity for these two sites. In view of these results and the fact that (-)-3-PPP has also been characterized as a dopamine antagonist at postsynaptic receptor sites in the striatum, (-)-3-PPP might be best described as a partial agonist at pituitary dopamine receptors. Moreover, these data are suggestive of a similarity, at least on a pharmacological basis, between dopamine autoreceptors and dopamine receptors in the anterior pituitary gland.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 239-246 |
| Number of pages | 8 |
| Journal | Life Sciences |
| Volume | 34 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jan 16 1984 |
Funding
Although similarities may exist between the dopamine receptor in the anterior pituitary gland and the dopamine autoreceptor, it does not appear that the pituitary dopamine receptor is a particularly useful model with which to assess the selectivity of action of dopamine agonist for the dopamine autoreceptor. Martin et al. (15) recently proposed an index of dopamine autoreceptor selectivity derived from the ratio of EDKn value for the production of stereotypy and the EDen value for the inhib1~ftion of DOPA accumulation in the striatum following ~--butyrolactone administration. These investigators observed a rank order for dopamine autoreceptor selectivity of TL-99 ~(+)-3-PPP~ NPA ~ bromocriptine~ apomorp~ine. In ~the present study, the IC50 values for the displacement of H-NPA or ~H-spiperone of the dopamin~ agonists we studied were not correlated with their putative selectivity for the dopamine autoreceptor. Acknowledgements The editorial assistance of Mrs. Georgia Gilbert is gratefully acknowledged. This work was supported by a Research Starter Grant from the PMA and by USPHS MH 30938 and by the Department of Mental Health, State of lllinois. HYM is recipient of USPHS MH 47808.
ASJC Scopus subject areas
- General Pharmacology, Toxicology and Pharmaceutics
- General Biochemistry, Genetics and Molecular Biology