Cyclic Analogues of Luteinizing Hormone-Releasing Hormone with Significant Biological Activities

There is evidence that, in its receptor-binding conformation, the N and C terminus of LH-RH may be in close proximity and two cyclic analogues of the hormone were synthesized to test the hypothesis. Cyclic [β-Ala¹,D-Ala⁶,Gly¹⁰]- and [6-aminohexanoic acid¹,D-Ala⁶,Gly¹⁰]-LH-RH were prepared by treatment of their linear precursor peptides with dicyclohexylcarbodiimide in the presence of 1-hydroxybenzotriazole in dilute dimethylformamide solution. Although the linear peptides possessed no detectable LH-releasing activity in ovariectomized rats, the cyclic β-Ala analogue had 1.2% the activity of LH-RH, whereas the longer chain cyclic 6-aminohexanoic acid analogue had 0.65% activity. These results support the concept of an important interaction between the ends of the LH-RH molecule possibly involving hydrogen-bond formation between the pyrrolidone carbonyl group of pyroglutamic acid and the glycinamide group.