Synthesis and biological activity of [D-Trp 6] chicken luteinizing hormone-releasing hormone

Abstract

An agonist of chicken hypothalamic luteinizing hormone-releasing hormone (cLH-RH). [D-Trp 6] cLH-RH, was synthesized and tested for luteinizing hormone (LH)-releasing activity using dispersed chicken anterior pituitary cells, as well as for binding to rat anterior pituitary membrane receptors. cLH-RH and mammalian LH-RH (mLH-RH) gave identical dose-response curves in stimulating chicken LH release ( ED 50=1.6 and 1.8×10 −9 M respectively) and similar estimates of potency. The [D-Trp 6] analogs of cLH-RH and mLH-RH stimulated LH release at lower doses ( ED 50=7.0 and ∼7.0×10 −11 M respectively) and were approximately 20-fold more potent. In contrast to the activity in the chicken bioassay, cLH-RH bound to rat anterior pituitary membrane receptors with a much lower affinity than did mLH-RH and had a relative potency of 2%. [D-Trp 6] cLH-RH was approximately 100-fold more potent than cLH-RH in the rat receptor assay while [D-Trp 6] mLH-RH was 28-fold more active than mLH-RH. These data demonstrate that substitution of Gly 6 of LH-RH with D-Trp enhances the LH release from chicken pituitary cells to a similar extent to that observed in mammals, and indicate that the approaches used to produce active LH-RH analogs in mammals are likely to be applicable to birds.