Agonist: Difference between revisions

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&nbsp;activated state<ref>David E. Golan, Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th Edition, Philadelphia, USA. 2016.</ref>. The affinity of the ligand to the receptor is determined through molecular forces such as (in order of least to greatest  
&nbsp;activated state<ref>David E. Golan, Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th Edition, Philadelphia, USA. 2016.</ref>. The affinity of the ligand to the receptor is determined through molecular forces such as (in order of least to greatest  


[[Image:Serotonin Receptor Interactions.jpg|frame|right|150x225px|Figure 1. Illustration of how the serotonin transmembrane receptor interacts with it's two agonists. Notice the blue molecule bound in the center.]]  
[[Image:Serotonin Receptor Interactions.jpg|frame|right|150x225px]]  


&nbsp;strength) [[Van der Waals forces|Vaan Der Vaals forces]], [[Ionic bond|ionic bonds]], [[Hydrogen Bonding|hydrogen bonds]] and [[Covalent Bonds|covalent bonds]]. The presence of the receptor in an activated conformation allows for (mainly) cytoplasmic protein interaction and [[Cell signalling pathways|transmission of the signal]] into the cell, and an associated response e.g. increased [[Gene expression|gene expression]]<ref>H.P Rang, J.M Ritter, R.J Flower and G. Henderson, Rang and Dale's Pharmacology, 8th Edition, Houston, USA. 2015.</ref>.&nbsp;  
&nbsp;strength) [[Van der Waals forces|Vaan Der Vaals forces]], [[Ionic bond|ionic bonds]], [[Hydrogen Bonding|hydrogen bonds]] and [[Covalent Bonds|covalent bonds]]. The presence of the receptor in an activated conformation allows for (mainly) cytoplasmic protein interaction and [[Cell signalling pathways|transmission of the signal]] into the cell, and an associated response e.g. increased [[Gene expression|gene expression]]<ref>H.P Rang, J.M Ritter, R.J Flower and G. Henderson, Rang and Dale's Pharmacology, 8th Edition, Houston, USA. 2015.</ref>.&nbsp;  
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<span style="font-size: 13.28px;">A greater amount of enzyme will increase the speed of [[Enzyme|synthesis]] of the final agonist, and thus increase it's effects. This provides insight into disease states, or predispositions to disease. Forexample, a lower expression of enzyme genes necessary to synthesize [[Serotonin|serotonin]] and [[Noradrenaline|noradrenaline]] can predispose people to lower mood states, and thus increase the likelihood of [[Major Depressive Disorder|depression]]</span><ref>Falk W. Lohoff, Overview of the Genetics of Major Depressive Disorder, Curr Psychiatry Rep, Dec 2010. 12(6) 539-549</ref><span style="font-size: 13.28px;">.&nbsp;</span>  
<span style="font-size: 13.28px;">A greater amount of enzyme will increase the speed of [[Enzyme|synthesis]] of the final agonist, and thus increase it's effects. This provides insight into disease states, or predispositions to disease. Forexample, a lower expression of enzyme genes necessary to synthesize [[Serotonin|serotonin]] and [[Noradrenaline|noradrenaline]] can predispose people to lower mood states, and thus increase the likelihood of [[Major Depressive Disorder|depression]]</span><ref>Falk W. Lohoff, Overview of the Genetics of Major Depressive Disorder, Curr Psychiatry Rep, Dec 2010. 12(6) 539-549</ref><span style="font-size: 13.28px;">.&nbsp;</span>  


[[Image:Dose Response Curve.jpg|left|300x175px|Figure 4. A dose response curve indicating the effect agonists and partial agonists have on an isolated living system e.g. a cell. ]]  
[[Image:Dose Response Curve.jpg|left|300x175px|Figure 4. A dose response curve indicating the effect agonists and partial agonists have on an isolated living system e.g. a cell.]]  


Agonists are not only classified by their [[Affinity|affinity]] to a given molecule (see first paragraph), but also by their efficacy. [[Efficacy|Efficacy]] is described as the ability of the agonists to stabilise the receptor into an activated state through a conformational change<ref>David E. Golan, Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th Edition, Philadelphia, USA. 2016.</ref>. A more full agonists will have the greatest efficacy possible and thus stabilise the receptor such that it remains active throughout the entirety of it's binding. A partial agonist will stabilise the receptor such that it remains active through only a portion of it's bound time. Comparatively, the full agonist will produce the greatest measurable response (e.g. cause complete myocyte contraction) while partial agonists produce a fraction of this (e.g. partial myocyte contraction)<ref>David E. Golan, Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th Edition, Philadelphia, USA. 2016.</ref>. A graph is shown to the left to illustrate this point. The [[Basal|basal response]] demonstrates the [[Constitutive Activity|constitutive]] activity of the receptor in the presence of non-stimulated endogenous ligand levels.&nbsp;  
Agonists are not only classified by their [[Affinity|affinity]] to a given molecule (see first paragraph), but also by their efficacy. [[Efficacy|Efficacy]] is described as the ability of the agonists to stabilise the receptor into an activated state through a conformational change<ref>David E. Golan, Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th Edition, Philadelphia, USA. 2016.</ref>. A more full agonists will have the greatest efficacy possible and thus stabilise the receptor such that it remains active throughout the entirety of it's binding. A partial agonist will stabilise the receptor such that it remains active through only a portion of it's bound time. Comparatively, the full agonist will produce the greatest measurable response (e.g. cause complete myocyte contraction) while partial agonists produce a fraction of this (e.g. partial myocyte contraction)<ref>David E. Golan, Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th Edition, Philadelphia, USA. 2016.</ref>. A graph is shown to the left to illustrate this point. The [[Basal|basal response]] demonstrates the [[Constitutive Activity|constitutive]] activity of the receptor in the presence of non-stimulated endogenous ligand levels.&nbsp;  
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Image references:  
Image references:  


1. David Goodsell, Serotonin Receptor, Unknown, 2013. URL: http://pdb101.rcsb.org/motm/164<br>
1. David Goodsell, Serotonin Receptor, Unknown, 2013. URL: http://pdb101.rcsb.org/motm/164<br>  


2. Frontiers, Stabilisation of G protein coupled receptors, Unknown, 2015. URL:&nbsp;https://www.frontiersin.org/files/Articles/133481/fphar-06-00082-HTML/image_m/fphar-06-00082-g005.jpg  
2. Frontiers, Stabilisation of G protein coupled receptors, Unknown, 2015. URL:&nbsp;https://www.frontiersin.org/files/Articles/133481/fphar-06-00082-HTML/image_m/fphar-06-00082-g005.jpg  


3. Amaia Sangrador and Alex Mitchell, Don't Blame The Cat, Unknown, 2014. URL: https://proteinswebteam.github.io/interpro-blog/2014/11/06/Don-t-blame-the-cat-the-toxoplasmosis-effect/
3. Amaia Sangrador and Alex Mitchell, Don't Blame The Cat, Unknown, 2014. URL: https://proteinswebteam.github.io/interpro-blog/2014/11/06/Don-t-blame-the-cat-the-toxoplasmosis-effect/  


4. Pharmakon, Dose-Response Curve, Unknown, Unknown. URL: https://pharmakondotme.wordpress.com/introduction/
4. Pharmakon, Dose-Response Curve, Unknown, Unknown. URL: https://pharmakondotme.wordpress.com/introduction/

Revision as of 14:53, 24 October 2017

An agonist is a ligand capable of binding to a receptor as a result of it's affinity to the given molecule, and causing a conformational change which stabilises the receptor in an

 activated state[1]. The affinity of the ligand to the receptor is determined through molecular forces such as (in order of least to greatest

 strength) Vaan Der Vaals forces, ionic bonds, hydrogen bonds and covalent bonds. The presence of the receptor in an activated conformation allows for (mainly) cytoplasmic protein interaction and transmission of the signal into the cell, and an associated response e.g. increased gene expression[2]. 

In terms of administration, agonists can be exogenous or endogenous molecules. The most 

Figure 2. Conformational change in a G protein coupled receptor, enabling activation of the associated G protein.
Figure 2. Conformational change in a G protein coupled receptor, enabling activation of the associated G protein.

common exogenous agonists that enter our body are actually unwanted, in contrast to desired administration of exogenous agonists e.g. medicines like morphine. Unwanted exogenous agonists can include chemicals produced in the work place, food additives, gaseous chemicals produced through pollution, second-hand smoke[3] etc.

<span style="font-size: 13.28px;" />Desired administration of exogenous agonists has many uses. Most salient amongst these are pleasure (e.g. from ethanol), therapeutic effects (e.g. from aspirin) or religious experiences (e.g. entheogens). 

Endogenous agonists are molecules, typically synthesized or modified using metabolic pathways, present without prior administration. This does not mean however, that their quantity in the body is not alterable. For example, different levels of precursors to the final, endogenous agonists affect the level of the ligand[4]. L-Dopa, a principal treatment for Parkinson's disease, is used in this way as it increases the levels of endogenous dopamine in the substantia nigra of affected patients. The level of gene expression is also important as it determines the quantity of enzymes capable of creating the final endogenous agonist.

Figure 3. Synthesis of dopamine with the use of various genetically encoded enzymes. Note the presence of L-DOPA which can be administered to treat Parkinsons.
Figure 3. Synthesis of dopamine with the use of various genetically encoded enzymes. Note the presence of L-DOPA which can be administered to treat Parkinsons.

<span style="font-size: 13.28px;" />

A greater amount of enzyme will increase the speed of synthesis of the final agonist, and thus increase it's effects. This provides insight into disease states, or predispositions to disease. Forexample, a lower expression of enzyme genes necessary to synthesize serotonin and noradrenaline can predispose people to lower mood states, and thus increase the likelihood of depression[5]. 

Figure 4. A dose response curve indicating the effect agonists and partial agonists have on an isolated living system e.g. a cell.
Figure 4. A dose response curve indicating the effect agonists and partial agonists have on an isolated living system e.g. a cell.

Agonists are not only classified by their affinity to a given molecule (see first paragraph), but also by their efficacy. Efficacy is described as the ability of the agonists to stabilise the receptor into an activated state through a conformational change[6]. A more full agonists will have the greatest efficacy possible and thus stabilise the receptor such that it remains active throughout the entirety of it's binding. A partial agonist will stabilise the receptor such that it remains active through only a portion of it's bound time. Comparatively, the full agonist will produce the greatest measurable response (e.g. cause complete myocyte contraction) while partial agonists produce a fraction of this (e.g. partial myocyte contraction)[7]. A graph is shown to the left to illustrate this point. The basal response demonstrates the constitutive activity of the receptor in the presence of non-stimulated endogenous ligand levels. 


References

  1. ↑ David E. Golan, Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th Edition, Philadelphia, USA. 2016.
  2. ↑ H.P Rang, J.M Ritter, R.J Flower and G. Henderson, Rang and Dale's Pharmacology, 8th Edition, Houston, USA. 2015.
  3. ↑ David E. Golan, Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th Edition, Philadelphia, USA. 2016.
  4. ↑ H.P Rang, J.M Ritter, R.J Flower and G. Henderson, Rang and Dale's Pharmacology, 8th Edition, Houston, USA. 2015.
  5. ↑ Falk W. Lohoff, Overview of the Genetics of Major Depressive Disorder, Curr Psychiatry Rep, Dec 2010. 12(6) 539-549
  6. ↑ David E. Golan, Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th Edition, Philadelphia, USA. 2016.
  7. ↑ David E. Golan, Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th Edition, Philadelphia, USA. 2016.



Image references:

1. David Goodsell, Serotonin Receptor, Unknown, 2013. URL: http://pdb101.rcsb.org/motm/164

2. Frontiers, Stabilisation of G protein coupled receptors, Unknown, 2015. URL: https://www.frontiersin.org/files/Articles/133481/fphar-06-00082-HTML/image_m/fphar-06-00082-g005.jpg

3. Amaia Sangrador and Alex Mitchell, Don't Blame The Cat, Unknown, 2014. URL: https://proteinswebteam.github.io/interpro-blog/2014/11/06/Don-t-blame-the-cat-the-toxoplasmosis-effect/

4. Pharmakon, Dose-Response Curve, Unknown, Unknown. URL: https://pharmakondotme.wordpress.com/introduction/

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