Synthesis and biological properties of [2 L β (pyrazolyl 3)alanine] luteinizing hormone releasing hormone

Article abstract of DOI:10.1021/jm00247a030

The LH RH activity of [Pyr(3)Ala²] LH RH was determined in vivo by the stimulation of LH release at 2 dose levels of 20 and 100 ng administered to ovariectomized rats (4 per group) which had been pretreated with estrogen and progesterone, followed by radioimmunoassay for LH. The serum LH contents were compared with those found after administration of controls with saline and 0.5 and 2.5 ng doses of LH RH isolated from natural sources. The biological potency of the analog was calculated to be high (19%) which clearly demonstrated that the properties peculiar to the imidazole ring of histidine are not essential for triggering of LH release to take place. This conclusion is supported by recent data accumulated from modifications of position 2. Deletion and also replacement of histidine with amino acids having nonfunctional or even functional side chains that are not aromatic in character result in peptides which are almost devoid of activity; however, incorporation of phenylalanine in this position gives a peptide which is 1-2% active. Thus, aromaticity is of some importance in promoting LH release. Tryptophan placed in position 2 results in a very high 40% retention of potency, presumably as a result of the combined effects of the ring systems and the slightly basic indole amine group. It is concluded that as long as aromatic side chains having some degree of basicity are present in position 2, then significant intrinsic levels of activity will remain.