Gonadotropin-Releasing Hormone (GnRH)
A 10 amino acid hypothalamic peptide controlling reproductive hormone release. Both GnRH agonists (goserelin, leuprolide, triptorelin, histrelin, nafarelin) and antagonists (cetrorelix, ganirelix, degarelix, relugolix, elagolix) are major drug classes for prostate cancer, endometriosis, fertility, and precocious puberty.
Technical Context
GnRH (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is a 10 amino acid peptide with both terminal modifications (N-terminal pyroglutamate, C-terminal amidation). The GnRH receptor is unique among GPCRs — it lacks a cytoplasmic tail, preventing beta-arrestin-mediated desensitisation. Instead, desensitisation relies entirely on receptor internalisation and transcriptional downregulation, which takes 1-2 weeks. Agonist modifications: position 6 substitution (D-amino acid — D-Ser(tBu), D-Leu, D-Trp, D-His(Bzl) — resists enzymatic cleavage and enhances receptor affinity), position 10 modification (des-Gly10 with ethylamide — enhances potency). These modifications increase half-life from ~4 minutes (native GnRH) to hours. The agonist class (goserelin, leuprolide, triptorelin, histrelin, nafarelin) shares this design strategy. Antagonist design requires bulkier substitutions at multiple positions to prevent receptor activation while maintaining binding.