Synthesis and biological activity of LH-RH antagonists modified in position 1

As part of our studies on the design of more potent antagonists of the LH-RH (luteinizing hormone-releasing hormone) decapeptide, twelve new highly soluble D-Arg⁶-analogs have been synthesized. These peptides contain modifications in position 1 and are typified by the general formula (N-acetyl-X¹, D-p-Cl-Phe², D-Trp³, D-Arg⁶, D-Ala¹⁰) LH-RH. We have found that a lypophilic, aromatic substituent is required in position 1 in order to elicit antiovulatory activity at a dose as low as 3 μg. The larger the hydrophobic amino acid (X: p-Br-Phe, β-Nal-2) in position 1, the higher is the antiovulatory activity that can be attained. Analogs with non-aromatic or hydrophilic amino acids (X: Gly, Leu, Arg, His, Glu) in position 1 generally have much lower activities in this series of LH-RH antagonists.     

Effect of an anti-substance P serum on prolactin and gonadotropins in hyperprolactinemic rats

The effects of the acute injection of a rabbit anti-substance P serum (ASPS) were studied in normal rats and rats with hyperprolactinemia induced by 5-hydroxytryptophan and estradiol given as a short or chronic treatment. The anti-substance P serum decreased the release of prolactin induced by 5-hydroxytryptophan when this serotonin precursor was injected 24 h, but not 1 h, after the administration of the antiserum. ASPS reduced the hyperprolactinemia induced by short and chronic treatment with estradiol in castrated rats. This effect was observed 24 h after the injection of the antiserum. On the other hand, the injection of ASPS induced a significant decrease in LH levels in serum of intact male rats injected with 5-hydroxytryptophan 24 h after ASPS, and in castrated rats treated with short-term and chronic administration of estradiol, 24 h after the injection of the antiserum. These results suggest that substance P may have a role in the control of prolactin secretion and could play a part in the hyperprolactinemic effects of estradiol. On the other hand, substance P, under certain circumstances, may stimulate LH release.     

Characterization, expression and function of DORMANCY ASSOCIATED MADS-BOX genes from leafy spurge

DORMANCY ASSOCIATED MADS-BOX (DAM) genes are related to AGAMOUS-LIKE 24 and SHORT VEGETATIVE PHASE genes of arabidopsis and are differentially regulated coordinately with endodormancy induction and release in buds of several perennial plant species. DAM genes were first shown to directly impact endodormancy in peach where a deletion of a series of DAM resulted in loss of endodormancy induction. We have cloned and characterized several MADS box genes from the model perennial weed leafy spurge. Leafy spurge DAM genes are preferentially expressed in shoot tips and buds in response to cold temperatures and day length in a manner that is relative to the level of endodormancy induced by various environmental conditions. Over-expression of one DAM gene in arabidopsis delays flowering. Additionally, we show that at least one DAM gene is differentially regulated by chromatin remodeling. Comparisons of the DAM gene promoters between poplar and leafy spurge have identified several conserved sequences that may be important for their expression patterns in response to dormancy-inducing stimuli.