Barrington J. A. Furr

Polypeptides. Part 15. Synthesis and biological activity of α-aza-analogues of luliberin modified in positions 6 and 10

Analogues of luliberin (luteinising hormone-releasing hormone) and 2-dehistidyl-luliberin containing α-azaglycine (–NHNHCO–) or α-aza-alanine (–NHNMeCO–) residues in either position 6 or 10 have been synthesised by classical procedures of peptide synthesis. The agonist and antagonist activities of these compounds were evaluated in androgen-sterilised constant-oestrus rats; [10-Azgly]-, [6-Azgly]-, and [6-Azala]-luliberin were marginally less active than the parent peptide. When the aza-change in position 6 was combined with an ethylamide substitution in position 10 the resulting compounds, [6-Azgly-10-de-Gly-NH2-9-Pro-ethylamide]- and [6-Azala-10-de-Gly-NH2-9-Pro-ethylamide]-luliberin, were twice as active as luliberin. [6-D-Ala-10-Azgly]luliberin was also twice as active as luliberin. [2-De-His-10-Azgly]-luliberin inhibited completely ovulation induced by luliberin (0.5 µg/rat) at a dose of 250 µg/rat, but 2-de-His-analogues of all the other compounds were devoid of antagonist activity in this test system.

Potent agonist and antagonist analogues of luliberin containing an azaglycine residue in position 10.

Potent agonist and antagonist analogues of luliberin containing an azaglycine residue in position 10 were synthesised and tested in androgen-sterilised constant-oestrus rats. The agonist, [D-Ser(But)6, Azgly10]-luliberin, induced ovulation at a dose of 6ng/rat i.v., 10μg/rat p.o. and was at least five times as potent as [D-Ser(But)6, des-Gly-NH210, Pro-ethylamide9]-luliberin. [D-Ser(But)6, Azgly10]-luliberin (1μg/rat) also prevented HCG-induced increases in ovarian and uterine weight in immature rats and was a highly potent antitumour agent when given to rats bearing DMBA-induced mammary tumours. The antagonist, [D-Phe2, D-Phe6, Azgly10]-luliberin at a dose of 15μg/rat completely inhibited ovulation induced by luliberin (0.5μg/rat), whereas [D-Phe2, D-Phe6]-luliberin lost activity below 125μg/rat.

Chapter 21. Luteinizing Hormone Releasing Hormone (LHRH) Analogues

Publisher Summary This chapter discusses the luteinizing hormone releasing hormone (LHRH) agonists and antagonists and their pharmacological activities and clinical applications. A number of LHRH agonists have entered clinical trial. Potent antagonists of LHRH show good in vivo activity. A few LHRH antagonists have recently been reported to be active by the oral route. Because LHRH analogues are poorly absorbed by the oral route, considerable effort has been expended to devise suitable formulations for clinical trials. LHRH agonists can stimulate gonadal function if given at low dose as a series of pulses. The combination of LHRH agonists with pure anti-androgens has also been studied in prostate cancer and preliminary results suggest that survival may be improved. The clinical utility of LHRH analogues in other forms of cancer remains to be determined. After treatment with LHRH analogues, responses have also occurred in post-menopausal women with breast cancer. The gonadal suppressing action of LHRH agonists as also been used to treat successfully precocious puberty in both boys and girls; preliminary results suggest that it has advantages over other available therapies. There has been widespread interest in the use of LHRH analogues as contraceptive agents and numerous studies have been conducted in primates and man. As many highly potent and safe LHRH agonists are available, there is room for improvement in the potency of LHRH antagonists and ideally in the identification of the orally active agents.

Polypeptides. Part 16. Synthesis and biological activity of α-aza-analogues of luliberin with high antagonist activity

Analogues of luliberin (luteinising hormone-releasing hormone) were synthesised where the glycine residue in position 10 was replaced by either azaglycine (–NH–NH–CO–) or aza-alanine (–NH–NMe–CO–), the histidine residue in position 2 was either omitted, or replaced by D-phenylalanine or D-tryptophan, and the glycine residue in position 6 was substituted either by D-phenylalanine or D-tryptophan. These compounds were evaluated for their ability to prevent ovulation induced by luliberin in androgen-sterilised constant-oestrus rats. Compounds with the azaglycine residue in position 10 and other modifications in positions 2 and 6 showed good antagonist activity, whereas aza-alanine replacement in position 10 together with modifications in position 2 resulted in inactive compounds. The most potent analogue, [2-D-Phe-6-D-Phe-10-Azgly]-luliberin, completely inhibited ovulation induced by luliberin (0.5 µg/rat) at a dose of 15 µg/rat.

SYNTHESIS AND BIOLOGICAL ACTIVITY OF α-AZAPEPTIDES: α-AZA-ANALOGUES OF LUTEINIZING HORMONE RELEASING HORMONE

The term ‘α‐azapeptides’is applied to analogues derived by change of one or more of the α‐CHs of amino‐acid residues in peptides by N; in such analogues the overall polarity of the molecule and the spacing of side‐chain residues is preserved, but stability towards peptidases may be increased because of the changed conformational situation at the residue or residues involved in the change. Three α‐aza‐analogues of LHRH, i.e. azaglycine6‐, azalanine10‐LHRH, and two α‐aza‐analogues of des‐His‐LHRH, i.e. azalglycine6‐and azalanine 6‐des‐His‐LHRH in inducing ovulation in androgen‐sterilized, constant‐oestrus rats, but less potent than LHRH in causing LH release in immature male rats. Evidence of increased duration of action was not obtained. The two aza‐analogues of des‐His‐LHRH were neither agonists nor antagonists in these two test systems.