This lecture by Dr. Kimberly Beck occurred on Wednesday, September 15th.
Required reading: Golan: 469-472
- Hypothalamic Hormoneshandout
- Hypothalamic Hormonesobjectives
Describe which sites on the GnRH decapeptide are cleaved enzymatically in vivo and how this affects the half-life of this hormone.Edit
Gonadotropin Releasing Hormone (GnRH) is enzymatically cleaved at two sites, which gives it a short half life in vivo of about 3-4 minutes. Either one or both of the will ultimately metabolize the hormone.
- Between Tyrosine 5 and Glycine 6
- Between Proline 9 and Glycine 10
Describe the rationale for the design of synthetic GnRH analogs.Edit
Synthetic analogues of GnRH are designed to stabilize the protein against enzymatic attack and increase binding to the GnRH receptor
- increasing the half life
- increasing potency
Unfortunately since the drugs are peptides, they can't be given orally. They must be given parenteraly (IV, SubQ, Intranasally)
Describe the relevance of incorporating D-amino acids in GnRH analogs.Edit
Normally all the amino acids used in the body are of the L-isomer form. But switching out the hydrophobic Glycine-6 with a D amino acid, it increases the half life of the GnRH analogue. Making the D-isomer of Glycine-6 bulky further increases receptor affinity. This increases potency 100-200x compared to natural GnRH
Describe the structure activity relationship of the GnRH agonists.Edit
- The PyroGlutamic adid 1, Histidine 2, and Tryptophan 3 are critical for biological potency of GnRH drugs.
- Any substitutions or deletions of these three amino acids will decrease or abolish receptor binding activity.
- When the glycine residue at position 6 is replaced with certain amino acids (combined with changes in the C-terminus) the proteolytic cleavage of the molecule is reduced, resulting in longer lasting action.
- All of the synthetic analogues of GnRH have a half life of about 4 hours. Coupled with the marked increase in potency, they are called superagonists.
Describe the mechanism of action of the GnRH agonists.Edit
Describe the structural features of the GnRH antagonists.Edit
The GnRH antagonists
- Are decapeptides, containing 10 amino acids
- Usually have the first 3 amino acids modified from the original PyroGlu-His-Trp
- Can contain up to 6 amino acid substitutions at the 1,2,3,6,8, and 10 positions.
- Compounds usually contain 3-5 substitutions
- The most potent antagonists (and there are only 2 available) contain the same D-amino acids at positions 1,2,3, and 10. The structural differences are at positions 6 and 8
Describe the mechanism of action of the GnRH antagonists.Edit
Given the sequence or structure of a GnRH analog, recognize whether it is an agonist or antagonist.Edit
Essentially a GnRH agonist will have identical residues to the first 3 of the natural compound. (PyroGlu-His-Trp) While an antagonist will have drastically different Ac-D-Nal(2)-D-Phe as its starting sequence