Cyclic analogs of luteinizing hormone-releasing hormone with significant biological activities

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Abstract
There is evidence that, in its receptor-binding conformation, the N and C terminus of LH-RH [luteinizing hormone releasing hormone] may be in close proximity and 2 cyclic analogs of the hormone were synthesized to test the hypothesis. Cyclic [.beta.-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[luteinizing hormone]-releasing activity in ovariectomized rats, the cyclic .beta.-Ala analog had 1.2% the activity of LH-RH, whereas the longer chain cyclic 6-aminohexanoic acid analog had 0.65% activity. 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 was supported.