Effective antagonists of luteinizing hormone releasing hormone modified at position one

Abstract

The amino acid, D-2-naphthylalanine, has been used by many investigators as a substituent for position one of antagonists of LHRH. We have newly designed substituents for position one in which the carboxy groups of 2-naphthoic acid, 3-quinoline- and 2-quinoxaline-carboxylic acids are linked to the five amino acids, DAla, DThr, DNVal, DSer, and Gly. The substituents in positions 2-10 were DpClPhe(2), DPal(3), Ser(4), PicLys(5), DPicLys(6), Leu(7), ILys(8), Pro(9), DAlaNH2 (10).Remarkably, DThr, acylated on the amino group by 3-quinolinecarboxylic acid or by 3-quinoxalinecarboxylic acid, and introduced into position one of a relatively potent antagonist, gave a new class of antagonists of LHRH, which released as little histamine as yet recorded, and yet possessed reasonable antiovulatory activity and greatly improved solubility.These structure-activity results advance the basic knowledge of understanding the structural features of such decapeptides which cause antiovulatory activity and histamine release.