GnRH analogues Flashcards
How can we use GnRH in a therapeutic manner ?
Continuous (low-dose/single dose high-dose):
SHUTTING DOWN:
Downregulation of gonadotrophin secretion
Shutting down of the hypothalamus when gonadal inhibition is medically required
Pulsatile mode of delivery: SWITCHING ON:
Upregulation of gonadotrophin secretion
Stimulates the gonads when required
How would GnRH agonists work?
They will bind to the GNRHR and trigger a cellular response leading to LH/FSH secretion.
However it will be shut down quickly because there is no downstream response
Binds for a much longer time to receptor than native GnRH
Causes cell response but ultimately downregulates GnRH receptor
Causes inhibition of that pathway
How would GnRH antagonists function?
They bind to the GnRHR and do not cause any downstream effects -immediately shut down
Binds really tightly to receptor (high efficacy) and blocks native GnRH from binding, preventing a cell response
Competitive inhibitor
Describe the structure of Native GnRH
Native GnRh is a Decapeptide
Highly conserved in most mammals, there are particular residues that are important for function so conserved among most species
(only change is amino acid substitutions)
Important residues for GnR
HR binding and activation
Pulsatile mode of deleivery means switching on the HPG axis
Synthetic GnRH has the exact same primary sequence as endogenous GnRH
Why do we need to use GnRH analogues as opposed to synthetic GnRH ?
1.GnRH has a very short half life (2-4 minutes in circulation)
2.To increase potency and duration of GnRH
(Analogues have been created -agonists/antagonists)
3.To manipulate the HPG axis in clinical practice -IVF , hormone responsive cancers and endometriosis
What is the difference between the Native GnRH and GnRH agonists which cause the agonist to shut down the axis ?
They have the same structure however Native GnRH has a shorter half life meaning it is degraded and leaves the receptor.
However the agonist will remain at the receptor for longer and this causes desensitisation.
What is the difference between the Native GnRH and GnRH agonists which cause the agonist to shut down the axis ?
They have the same structure however Native GnRH has a shorter half life meaning it is degraded and leaves the receptor.
However the agonist will remain at the receptor for longer and this causes desensitisation as it does not dissociate.
How can we manipulate the structure of GnRH ?
It is naturally a decapeptide meaning it contains 10 mino acids.
The parts which are usually highly conserved are positions 1-4 and 9-10 + amide group.
The amino acid substitutions will rarely occur in these positions.
The C-terminus residues: very important for receptor binding only
The N-terminus residues: for receptor binding AND activations
Arginine: is the most variable and so is responsible for species-ligand specificity
Glycine: enhance activity of analogue (d-amino acid substitutions)
D amino-acid substitutions are isomers and are more resistant to proteolytic cleavage and tricks the body to keeping GnRH analogues present for longer
How can we create GnRH agonists ?
Making an agonist & antagonist:
Substitutions of Glycine by D-aa
Stabilises conformation and enhances activity
Changes structure of GnRH to be more potent
Some analogues have a replacement of the C-terminus by NH2- ethylamide binding to Pro (position 9/10)
How can we create an antagonist ?
Not as simple as making an agonist
Took 30 years to make
1st Gen Antagonists:
Replaces His & Trp at position 2 & 3, but low in suppressive activity
2nd Gen Antagonists:
Potency increased by using D-aa substitution in position 6
But causes anaphylaxis by histamine release
3rd Gen Antagonists:
Replaces D-Arg by D-ureidoalkayl aa
