Synthesis and biological evaluation of novel structure-related hGHRH agonistic analogs

Abstract

Activity and half-life play key roles in the application of GHRH analogues. The GHRH monomers produced in a solid synthesizer were incubated, respectively, in NH4OH solution and lyophilized to obtain their dimers. The activities, specificities, and receptor affinities of the GHRH dimers were evaluated in rGH release/inhibition, rACTH/LH/PRL release, pituitary homogenate binding, and fluorescent staining. Compared to hGHRH(1-44)NH2 (S), PP-hGHRH(1-44)-GGC-CGG-hGHRH(44-1)-PP (2D), P-hGHRH(1-44)-GGC-CGG-hGHRH(44-1)-P (2E), (1)P-hGHRH(2-44)-GGC-CGG-hGHRH(44-2)-(1)P (2F), or hGHRH(1-44)-GGC-CGG-hGHRH(44-1) (2Y) had potency of 104 ± 16.7%, 94 ± 32.6%, 114 ± 16.6%, or 122 ± 14.5% and similar specificities. The inhibition effect of GHIH on rGH stimulated by GHRH dimer was in dose-/time-dependent manner. The staining of FITC-labeled dimer showed cytomembrane distribution and the binding ranking was 2F>2D>2Y>2E>S. 2F presents the strongest activity and the highest affinity to pituitary cells. The dimer with (1)Pro-GHRH stimulates stronger rGH release than that with (1)Tyr-GHRH and the N-terminal single cyclic amino acid is required for the stimulation.

Agonists of growth hormone-releasing hormone (GHRH) inhibit human experimental cancers in vivo by down-regulating receptors for GHRH

“…Acting as an autocrine/paracrine growth factor, GHRH also exerts direct effects on various extrapituitary cells or tissues, mediated by GHRH receptors (GHRH-Rs) (1)(2)(3)(4). In the past decades, many analogs of GHRH have been synthesized (1)(2)(3)(4)(5)(6)(7). Our laboratory has developed several classes of GHRH antagonists that show potent inhibitory effects on the growth of various tumors (1)(2)(3)(4)(5)7).…”

The treatment effect of novel hGHRH homodimer to male infertility hamster

“…Moreover the GH has stronger expression than the GHRH receptor. Although Grin has the significant in vitro pituitary GH release [ 14 ], in vivo the Grin doses did not induce pituitary or testicular GH release, suggesting that the fertility effects of Grin on the models were not mediated by GH. Also, the insignificant alteration in serum and testicular GHs may reflect that Grin had an insufficient dose which did not trigger pituitary GH secretion, or more affinity to injury testes instead of pituitary.…”

“…Grin monomer and FITC-labeled hGHRH(1-44)NH 2 peptides were synthesized in the solid phase polypeptidesynthesis ( China Peptides Co., Ltd , China). Grinwas synthesized in a special dimerization protocol [ 14 ]. The amino acid sequences of these hGHRH peptides were referred to Table 1 .…”

“…In our previous publication [ 14 ], Grin peptide (also known as 2F) showed the strongest and long-lasting in vitro effect on rat GH release and similar species-specificity compared to natural hGHRH(1-44)NH 2 . Up to now no publication about hGHRH agonist was reported in the pharmacodynamics of infertility.…”