Neuropharmacology: full agonists, partial agonists and constitutively active receptors (Dr. Moss) Flashcards
Why does a conformational change occur when an agonist bind to a reeptor ?
Because on binding an agonist molecule the receptor is able to make bonds (e.g. H-bonds, charge-charge interactions, hydrophobic interactions etc.) that favor the receptor occupying the active conformation.
Is the conformational change that pushes the receptor into the active conformation reversible ?
Why ?
Yes, because at some point the receptor-agonist complex will have enough thermal energy to break the bonds that hold them in the active conformation.
What is the Del Castillo-Katz model of receptor activation ?
A + R = AR = AR*
AR –> binding
AR* –> conformational change to an active state
This was first model to separate agonist binding and receptor gating steps in the pathway towards receptor activation.
What does the seperate step for receptor activation in the Del Castillo-Katz model suggest ?
It embodies the idea of agonist efficacy – the ability of the agonist to stabilise the active state of the receptor.
What are full agonists ?
Drugs that elicit maximal tissue response.
What are partial agonists ?
Drugs that cannot elicit maximal tissue response no matter how high their concentration.
What are examples of full agonists/partial agonists acting at the beta-adrenoreceptors ?
Full agonists: adrenaline, isoprenaline
Partial agonists : prenalterol
What are examples of full agonists/partial agonists acting at the histamine H2 receptors ?
Full agonists: histamine
Partial agonists: impromidine
How can we rule out the idea that partial agonists are not able to combine with all the receptors (and therefore cannot elicit maximal response) ?
By testing the effect of increasing concentrations of a partial agonist on the response of a tissue to a fixed concentration of a full agonist. As the concentration of the partial agonist is raised, the response of the tissue gradually falls from the large value seen with the full agonist alone, and eventually reaches the maximum response to the partial agonist acting on its own.
How can the Del Castillo-Katz model account for the difference between partial and full agonist ?
The Del Castillo-Katz model shows that the crucial difference between a partial agonist and a full agonist lies in their ability to activate (rather than bind to) the receptor, and stabilize that active conformation.
How did the patch clamp technique, allowing single channel recordings, validate the Del Castillo-Katz model ?
Most of the time, the nACh channels is closed, waiting for an agonist molecule to arrive. When agonist and receptor form a complex the channel opens in a ‘burst’ of activity. The long shut times are periods where the channel is waiting to associate with another agonist molecule. The brief shut times however, are surrounded by openings and this ‘burst’ of activity corresponding rapid transitions between the AR and the AR* state during which time the ligand is always bound.
What are Slow-Channel Congenital Myasthenic Syndromes (SSCMSs) ?
SCCMSs are disorders of NM transmission. They are characterized by muscle weakness and fatigability. Although a variety of mutations cause SCCMS, all SCCMS mutations produce prolonged endplate currents.
What is the consequence of SSCMS at single channel level ?
The response of a channel carrying mutation epsilon L78P for example will stay open much longer. Detailed analysis reveals that such mutants differ in ACh efficacy and binding.
How did the crystal structures of full and partial alpha 1 adrenoreceptor agonists reveal the crucial role of receptor stabilization (Warne et al., 2011, Nature 469, 241) ?
These showed that both full and partial agonists encourage the same conformational change in the receptor. However, the full agonist isoprenaline was able to stabilize that conformation by making 2 H-bonds with serine residues 211 and 215 of the receptor, while the partial agonist dobutamine could only make a H-bond w/ serine 211.
How can a receptor be constitutively active ?
Sometimes, by chance, random collisions can provide the thermal energy that is required to for the receptor to enter the active state in absence of an agonist –> constitutively active receptor