This lecture by Dr. Kimberly Beck occurred on Wednesday, September 15th.
Study materials[]
Required reading: Golan: 469-472
Handouts[]
- Hypothalamic Hormoneshandout
- Hypothalamic Hormonesobjectives
Panopto[]
Objectives[]
Describe which sites on the GnRH decapeptide are cleaved enzymatically in vivo and how this affects the half-life of this hormone.[]
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.[]
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.[]
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.[]
- 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.[]
Describe the structural features of the GnRH antagonists.[]
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.[]
Given the sequence or structure of a GnRH analog, recognize whether it is an agonist or antagonist.[]
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