analogs can differentiate between pituitary and CNS receptors: homo-pyroGlu-His-
Pro-NH 2 (5.70) is equipotent to TRH in the pituitary but about 10 times more active in
the CNS.
Antagonists of TRH have also been synthesized. For example, cyclopentylcarbonyl-
thienylalanyl-pyrrolidine amide inhibits TSH release at high doses. Thyroliberin is used
diagnostically only, to distinguish between hypothalamic and pituitary hypothyroidism.
5.15.2.3 Gonadoliberin
Gonadoliberin (gonadotropin releasing hormone, GnRH; luteinizing hormone-releasing
factor, LHRH) releases gonadotropins,lutropin(LH) and follitropin(FSH). It was first
isolated and synthesized by the Schally group and has an identical structure in all
vertebrates: pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2. Gonadoliberin does
not release equal amounts of LH and FSH. Apparently, GnRH synthesis is under
GABAergic control and acts through adenylate cyclase.
Agonist and “superagonist” analogs of GnRH have been prepared among the more
than 1000 compounds investigated. The [D-Trp^6 ,Pro^9 - N-Et] and [D-Ala^6 ,N-Me-Leu^7 ]
analogs (where the superscript indicates the amino acid position in the original peptide)
have a 150-fold greater activity than GnRH. Many of these highly active analogs have
a long-lasting action because the D-amino acids in their structure prevent attack by pro-
teolytic enzymes. Additionally, they are active not only parenterally (by injection) but
also as nasal sprays or intravaginal suppositories. Some of the agonists that have been
prepared include leuprolide (5.71), nafarelin (5.72), goserelin (5.73), and histrelin
(5.74). An inspection of these structures suggests the structure–activity relationships.
For example, D-amino acids at position 6 and ethylamide substituents for glycine at
position 10 tend to increase duration of action and potency.
342 MEDICINAL CHEMISTRY