Effective antagonists of luteinizing hormone releasing hormone modified at position one

Summary 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 DpClPhe², DPal³, Ser⁴, PicLys⁵, DPicLys⁶, Leu⁷, ILys⁸, Pro⁹, DAlaNH₂¹⁰.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.Abbreviations ILys N-isopropyllysine; - 1-Nal 3-(1-naphthyl)alanine - 2-Nal 3-(2-naphthyl)alanine - Nap 2-naphthoic acids - NicLys N-nicotinoyllysine; - Pal 3-(3-pyridyl)alanine - pClPhe 3-(4-chlorophenyl)alanine - PicLys N-picolinoyllysine - c-PzACAla cis-3-(4-pyrazinylcarbonylaminocyclohexyl) alanine - 3-Qal 3-(3-quinolyl)alanine - Qui 3-quinolinecarboxylic acid - Qux 2-quinoxalinecarboxylic acid