Design and synthesis of potent tyr(OMe)5-gonadotropin-releasing hormone (GnRH) analogues with modifications at positions 6, 9 and 10 |
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Authors: | Maria Keramida John M Matsoukas George Agelis Dimitris Panagiotopoulos John Cladas Debanada Pati Graham J Moore and Hamid R Habibi |
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Institution: | (1) Department of Chemistry, University of Patras, 26500 Patras, Greece;(2) Thalassa Fish Hatchery, 33056 Hiliadou Doridos, Greece;(3) Department of Biological Sciences, University of Calgary, Calgary, Alberta, T2N 1N4, Canada;(4) Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, T2N 4N1, Canada |
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Abstract: | We have recently reported the synthesis and the conformational properties of some Gonadotropin-releasing hormone (GnRH) analogues in which the tyrosine residue at position 5 is substituted with tyrosine-O-methyl (Keramida et al., Let. Pept. Sci., 3 (1996) 257/Matsoukas et al., Eur. J. Med. Chem., 32 (1997) 927). The analogue Tyr-(OMe)5]-GnRH was found to exert a lower degree of desensitization than the native GnRH peptides in terms of pituitary gonadotropin (GTH) release in goldfish. Compared to GnRH, however, Tyr-(OMe)5]-GnRH exerted a lower GTH-release potency in cultured goldfish pituitary fragments, and was bound with a lower binding affinity to the rat pituitary GnRH receptors. In order to increase the potency of Tyr-(OMe)5]-GnRH, we have synthesized a group of GnRH peptides containing Tyr-(OMe)5 in combination with other substitutions at positions 6, 9 and 10 and we have estimated their binding affinity for the rat pituitary receptors and gonadotropin (GTH) release potency in the goldfish pituitary. A selected number of these analogues was also tested for their ability to induce ovulation in seabass. The important structural modifications that increased the binding and gonadotropic activity of Tyr(OMe)5]-GnRH in vitro and in vivo were found to include the replacement of the proline at position 9 with azetidine, glycine amide terminus with an alkyl amide group and Gly6 residue with hydrophilic D-amino acids such as D-Arg6. Overall, the findings provide SAR information on a group of novel GnRH peptides that can be also used to induce ovulation in teleosts. |
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Keywords: | fish gonadotropin release Gonadotropin-Releasing Hormone (GnRH) peptide analogues receptor binding |
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