Differing affinities for subtypes by natural endogenous ligands to their own receptor

[Nagelfar]

Does anybody know the affinity of *dopamine itself* for the various D₁-D₄ receptor subtypes or a good resource on that topic? I have the same question about serotonin, or any other endogenous neurotransmitter if the info is at hand would be of interest to me for the purposes of this thread topic.

 

[serotonin2A]

http://kidbdev.med.unc.edu/database...=&KiLess=&kiAllRadio=all&doQuery=Submit+Query

 

[Nagelfar]

http://kidbdev.med.unc.edu/database...=&KiLess=&kiAllRadio=all&doQuery=Submit+Query

It's a little tough to suss out for me;

So for D1, dopamine has a Ki of 17.5 against 3H labeled dopamine as hot ligand, 38.30 Ki for DAT against 3H DA, but no other hot ligands seem to give any kind of spread with viable similarity-maximized comparison compounds.

 

[serotonin2A]

but no other hot ligands seem to give any kind of spread with viable similarity-maximized comparison compounds.

I don't understand what that means...can you clarify?

 

[Seppi]

Does anybody know the affinity of *dopamine itself* for the various D₁-D₄ receptor subtypes or a good resource on that topic? I have the same question about serotonin, or any other endogenous neurotransmitter if the info is at hand would be of interest to me for the purposes of this thread topic.

See sections "Selectivity at human GPCRs" and "Selectivity at human ion channels"
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=940
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=5

 

[Cotcha Yankinov]

So for D1, dopamine has a Ki of 17.5 against 3H labeled dopamine as hot ligand, 38.30 Ki for DAT against 3H DA, but no other hot ligands seem to give any kind of spread with viable similarity-maximized comparison compounds.

Do you mean to say that dopamine has a narrow variation of affinity for different sites compared to non-endogenous ligands that may have much wider variations in affinity?

 

[serotonin2A]

Don't forget that there is both phasic and tonic dopamine signaling. During phasic release, synaptic dopamine concentrations reach high micromolar levels. So the Ki is probably only relevant to tonic dopamine responses (because receptors would be saturated by phasic signaling).

 

[Nagelfar]

I don't understand what that means...can you clarify?

Sorry, convoluted even for me there. I mean what would be a way of finding a definite litmus for what level of affinity; comparable to DA, would be a standard to denote other dopamine receptor agonists as super-agonists, equivalent agonists or partial agonists. I am wondering if an example of a compound might exist with a wide spread of affinity which can have inverse proportion to DA itself but still displaying affinity for all subtypes: e.g. D1-4, if dopamine has most at one, theoretically compound would have least (but still appreciable affinity) at that one, and whichever DA had least affinity for, theoretical compound would have most affinity at that subtype.

 

[serotonin2A]

Sorry, convoluted even for me there. I mean what would be a way of finding a definite litmus for what level of affinity; comparable to DA, would be a standard to denote other dopamine receptor agonists as super-agonists, equivalent agonists or partial agonists. I am wondering if an example of a compound might exist with a wide spread of affinity which can have inverse proportion to DA itself but still displaying affinity for all subtypes: e.g. D1-4, if dopamine has most at one, theoretically compound would have least (but still appreciable affinity) at that one, and whichever DA had least affinity for, theoretical compound would have most affinity at that subtype.

Efficacy and affinity are independent, and you can't make valid conclusions about efficacy based on affinity in competitive binding experiments.

 

[Nagelfar]

Efficacy and affinity are independent, and you can't make valid conclusions about efficacy based on affinity in competitive binding experiments.

I understand that, I never mentioned efficacy; I mean solely affinity of theoretical compound as against DA itself for the D1-4 receptors and possible inversion of affinity spread.

 

[serotonin2A]

I understand that, I never mentioned efficacy; I mean solely affinity of theoretical compound as against DA itself for the D1-4 receptors and possible inversion of affinity spread.

I see. My confusion stems from the following quote, which seems to be asking about classifying drugs based on efficacy:

I mean what would be a way of finding a definite litmus for what level of affinity, comparable to DA, would be a standard to denote other dopamine receptor agonists as super-agonists, equivalent agonists or partial agonists.

 

[Nagelfar]

I see. My confusion stems from the following quote, which seems to be asking about classifying drugs based on efficacy:

Should have said "such as" my apologize but I think my mind was drifting on how else they could be tabled.