Analogs of luteinizing hormone-releasing hormone with increased biological activity produced by D-amino acid substitutions in position 6

The incorporation of simple d-amino acids in place of glycine in position 6 of the LH-RH decapeptide produces analogs which have far greater gonadotropin-releasing activities in vivo and in vitro than the natural hormone. An investigation of the structural features of the d-amino acids responsible for this phenomenon suggests that an increase in the lipophilic character and perhaps the size and aromaticity of the side chain coincides with an increase in biological activity. This is demonstrated by the LH-releasing activities of the following series of Peptides which were assayed over a period of 6 h in immature male rats: [d-Glu(6)]-,1.8;[d-Ala(6)]-,7.0;[d-Leu(6)]-,9,0;[d-Phe(6)]-,10;[d-Trp(6)]-LH-RH, 13 times more active than LH-RH itself. In contrast to previous results with [d-Ala(6)]-and [d-Leu(6)]-LH-RH, where the substitution of an ethylamide group for the glycine amide at the C-terminus produces large increases in LH/FSH releasing activity, the ethylamide derivatives of [d-Phe(6)]-and [d-Trp(6)]-LH-RH were actually less potent than their parent Peptides. [(N-Me-d-Ala)(6)]-LH-RH was found to be approximately 70 times less active than [d-Ala(6)]-LH-RH which indicates that disruption of a preferred receptor-site binding conformation might be brought about by methylation of the amide linkage in this position.