A Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH2 B Arg Gln Lys-Val

C Arg Gln Lys-Val

D Arg Gln Lys-Val

E Arg Gln Lys-Val

F Arg Gln-Arg-Ser Phe-Asn-OH

aAmino-acid sequences of A, hpGHRF(1-44)NH2; B, porcine GHRH; C, bovine GHRH; D, bovine GHRH; E, caprine GHRH; F, rat GHRH.

the poor GH responses achieved with the natural peptides. Indeed, the first-phase plasma disappearance rate of GHRH(1-40) measured by RIA in men is only in the region of 8 min (19). There have been a number of studies aimed at elucidating the metabolism of GHRH using both the natural sequences and stabilized synthetic analogs sequences. The latter will be discussed in subsequent analog sections of this chapter. Interestingly, the primary cleavage point of all the GHRHs in human plasma is at the 2-3 peptide bond, which is hydrolysed by a dipeptidylpeptidase IV enzyme (20). After removal of the N-terminal dipeptide, little further N-terminal degradation from the 3 position onwards seems to occur. Tryptic degradation at the 11-12 and, depending on the total length of the peptide, at position 12-13 was also noted (20). Similarly, in pig plasma the half-life of GHRH(1-29)NH2 was around 13 min (21) with GHRH(3-29)NH2 being the major metabolite. Evidence of deamidation of the Asn residue in position 8 of GHRH by incubation in aqueous solution at neutral pH has also been reported (22). Overall then, there is an excellent medicinal rationale for developing enzyme-resistant, high-affinity GHRH analogs.

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