The first antagonist of GHRH was found (55) by accident during an evaluation of N-terminally modified analogs for binding and activation of the rat pituitary GHRH receptor. Although D-Ala2-GHRH(1-29)NH2is, as we have discussed, a potent agonist, Ac-Tyr1 ,D-Arg2-GHRH(-29)NH2 was found to be devoid of GHRH agonist activity and a moderately good antagonist, thus providing additional proof that this part of the GHRH chain comprises the active center of the molecule. As mentioned, another weaker antagonist was produced by introduction of a reduce dipeptide bond into the 9-10 sequence of GHRH(1-29)NH2 (45).
The antagonist potency of the D-Arg2-analogs has since been improved upon by the use of combined additional alterations to the peptide chain, such as Ala15 (56), Ala8,9 (51), and agmantine incorporation at the C-terminus (57). Ac-Tyr1,D-Arg2-GHRH(-29)NH2 was quite effective in blocking pulsatile basal GH secretion and somatic growth in rats (58) and could block the effects of GHRH at both the hypothalamic and pituitary level after micro-injection (59). Similarly, high doses of the same analog were able to block GH release in normal human subjects, although its inhibitory potency was relatively weak (60). Constant infusion of an agmantine-containing GHRH antagonist was reported (61) to be able to slow the growth of human osteosarcomas transplanted in nude mice and to lower IGF-1 levels in the treated animals.
Interestingly, introduction of D-Phe in position 2 of a GHRH analog, Ac-Tyr1 ,D-Phe2-GHRH(1-29)NH2, created a VIP receptor antagonist (62) with weak GHRH agonist activity. This analog cannot be considered the best choice of VIP antagonist because it has quite weak binding and partial VIP agonist activity in some biological systems (63).
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