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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 17 of 17. This is the beginning of the thread.
Posted by kotsunega on June 16, 2003, at 16:01:37
Zyprexa has sedating properties that the other atypical antipsychotics don't share to any real degree. What makes Zyprexa so sedating? I found an Aripiprizole receptor binding chart (http://sl.schofield3.home.att.net/medicine/aripiprazole_binding.pdf) that compares the receptor binding properties of Abilify to other atypical antipsychotics, but I don't see a relationship between the degree of binding for any receptor with Zyprexa, unless it's the 5HT1A receptor for which Zyprexa has a very strong affinity. Could this be what causes it's sedating action?
Posted by Caleb462 on June 16, 2003, at 18:04:12
In reply to What is it about Zyprexa that makes it so sedating, posted by kotsunega on June 16, 2003, at 16:01:37
> Zyprexa has sedating properties that the other atypical antipsychotics don't share to any real degree. What makes Zyprexa so sedating? I found an Aripiprizole receptor binding chart (http://sl.schofield3.home.att.net/medicine/aripiprazole_binding.pdf) that compares the receptor binding properties of Abilify to other atypical antipsychotics, but I don't see a relationship between the degree of binding for any receptor with Zyprexa, unless it's the 5HT1A receptor for which Zyprexa has a very strong affinity. Could this be what causes it's sedating action?
You're looking at the chart wrong, the HIGHER the number, the LOWER the affinity. Small numbers signify high affinity.So, looking at it now you'll see... Zyprexa is a fairly strong ANTAGONIST at EVERY dopamine receptor. Where as the other atypicals display strong affinity for a couple of dopamine receptors, and somewhat lesser affinity for the others.. I think this plays a part.
You'll also see that zyprexa is the strongest anti-histamine, other than clozaril, out of the bunch. It's also tied for with clozaril for most anti-chollinergic, and it's anti-adrenergic effects are pretty strong too. Overall, it works out on paper as the most sedating atypical.
Posted by kotsunega on June 16, 2003, at 20:06:42
In reply to Re: What is it about Zyprexa that makes it so sedating, posted by Caleb462 on June 16, 2003, at 18:04:12
Thanks, but I'm still confused a little. What exactly does high affinity mean? I thought it meant the degree of attraction to a specific receptor, but from your post, it sounds like I've got that wrong. Please explain if you can.
Thanks much,
-kotsunega
Posted by Caleb462 on June 16, 2003, at 23:35:23
In reply to Re: What is it about Zyprexa that makes it so sedating, posted by kotsunega on June 16, 2003, at 20:06:42
> Thanks, but I'm still confused a little. What exactly does high affinity mean? I thought it meant the degree of attraction to a specific receptor, but from your post, it sounds like I've got that wrong. Please explain if you can.
No, you've got it right.
Posted by cybercafe on June 17, 2003, at 0:24:40
In reply to Re: What is it about Zyprexa that makes it so sedating, posted by Caleb462 on June 16, 2003, at 23:35:23
> > Thanks, but I'm still confused a little. What exactly does high affinity mean? I thought it meant the degree of attraction to a specific receptor, but from your post, it sounds like I've got that wrong. Please explain if you can.
>
> No, you've got it right.
>
>i'm curious as to what is going on in the physical sense..... i mean receptors don't really 'attract' molecules right?
hmmm
Posted by Caleb462 on June 17, 2003, at 0:30:53
In reply to Re: What is it about Zyprexa that makes it so sedating, posted by cybercafe on June 17, 2003, at 0:24:40
> > > Thanks, but I'm still confused a little. What exactly does high affinity mean? I thought it meant the degree of attraction to a specific receptor, but from your post, it sounds like I've got that wrong. Please explain if you can.
> >
> > No, you've got it right.
> >
> >
>
> i'm curious as to what is going on in the physical sense..... i mean receptors don't really 'attract' molecules right?
> hmmmI should have stated this - affinity means how a molecule FITS in a receptor. I think that is all there is to it, but I could be wrong.. anyone care to enlighten?
Posted by Caleb462 on June 17, 2003, at 0:31:41
In reply to Re: What is it about Zyprexa that makes it so sedating, posted by Caleb462 on June 17, 2003, at 0:30:53
> > > > Thanks, but I'm still confused a little. What exactly does high affinity mean? I thought it meant the degree of attraction to a specific receptor, but from your post, it sounds like I've got that wrong. Please explain if you can.
> > >
> > > No, you've got it right.
> > >
> > >
> >
> > i'm curious as to what is going on in the physical sense..... i mean receptors don't really 'attract' molecules right?
> > hmmm
>
> I should have stated this - affinity means how a molecule FITS in a receptor. I think that is all there is to it, but I could be wrong.. anyone care to enlighten?How WELL a molecule fits, that is.
Posted by kotsunega on June 17, 2003, at 11:40:10
In reply to Re: What is it about Zyprexa that makes it so sedating, posted by Caleb462 on June 17, 2003, at 0:31:41
> > > > > Thanks, but I'm still confused a little. What exactly does high affinity mean? I thought it meant the degree of attraction to a specific receptor, but from your post, it sounds like I've got that wrong. Please explain if you can.
> > > >
> > > > No, you've got it right.
> > > >
> > > >
> > >
> > > i'm curious as to what is going on in the physical sense..... i mean receptors don't really 'attract' molecules right?
> > > hmmm
> >
> > I should have stated this - affinity means how a molecule FITS in a receptor. I think that is all there is to it, but I could be wrong.. anyone care to enlighten?
>
> How WELL a molecule fits, that is.
Posted by Ritch on June 17, 2003, at 13:07:48
In reply to Re: What is it about Zyprexa that makes it so sedating, posted by Caleb462 on June 17, 2003, at 0:30:53
> > > > Thanks, but I'm still confused a little. What exactly does high affinity mean? I thought it meant the degree of attraction to a specific receptor, but from your post, it sounds like I've got that wrong. Please explain if you can.
> > >
> > > No, you've got it right.
> > >
> > >
> >
> > i'm curious as to what is going on in the physical sense..... i mean receptors don't really 'attract' molecules right?
> > hmmm
>
> I should have stated this - affinity means how a molecule FITS in a receptor. I think that is all there is to it, but I could be wrong.. anyone care to enlighten?Ok-I read this a LONG time ago, but from what I remember the "numbers" that you see (with regard to "affinity") have to do indirectly with the number of molecules of a given substance it takes to bind to 50% of the receptors (I think outside the body in a dish-but it is close enough analog of what happens in the body that it is useful info). So a high number means that a LOT of the substance is required to bind to 50% of the receptors or something along those lines. Of course-this needs to be clarified a lot, I'm sure, but I think that *generally* that is somewhat true.
Posted by kotsunega on June 17, 2003, at 17:09:38
In reply to Re: What is it about Zyprexa that makes it so sedating » Caleb462, posted by Ritch on June 17, 2003, at 13:07:48
> > > > > Thanks, but I'm still confused a little. What exactly does high affinity mean? I thought it meant the degree of attraction to a specific receptor, but from your post, it sounds like I've got that wrong. Please explain if you can.
> > > >
> > > > No, you've got it right.
> Ok-I read this a LONG time ago, but from what I remember the "numbers" that you see (with regard to "affinity") have to do indirectly with the number of molecules of a given substance it takes to bind to 50% of the receptors (I think outside the body in a dish-but it is close enough analog of what happens in the body that it is useful info). So a high number means that a LOT of the substance is required to bind to 50% of the receptors or something along those lines. Of course-this needs to be clarified a lot, I'm sure, but I think that *generally* that is somewhat true.
Thanks, Ritch. Your description helps me understand the relationship of higher numbers to lower affinity. - Appreciate that. : )-kotsunega
Posted by fachad on June 17, 2003, at 17:45:22
In reply to What is it about Zyprexa that makes it so sedating, posted by kotsunega on June 16, 2003, at 16:01:37
I think the reason that receptor affinity numbers seem backwards is that they are really inverse values, that is 1/x, but usually just the denominator (bottom number of the fraction) is given by itself.
Maybe for printing convenience.
But if you look at it that way, then of course the higher the number, the lower the value (1/5 is much higher than 1/500).
Hope that clears it up.
Posted by Larry Hoover on June 18, 2003, at 9:39:43
In reply to Re: What is it about Zyprexa that makes it so sedating, posted by kotsunega on June 17, 2003, at 17:09:38
> > > > > > Thanks, but I'm still confused a little. What exactly does high affinity mean? I thought it meant the degree of attraction to a specific receptor, but from your post, it sounds like I've got that wrong. Please explain if you can.
Actually affinity is defined in terms of the likelihood of the ligand (the substance binding to the receptor) releasing itself from the receptor site. In other words, affinity is defined as the inverse of dissociation. I'll explain more fully in a moment.
> > > > >
> > > > > No, you've got it right.
> > Ok-I read this a LONG time ago, but from what I remember the "numbers" that you see (with regard to "affinity") have to do indirectly with the number of molecules of a given substance it takes to bind to 50% of the receptors (I think outside the body in a dish-but it is close enough analog of what happens in the body that it is useful info).No, sorry. That's the IC50, or EC50. That's the concentration of a ligand which has the physiological effect of inhibiting or exciting 50% of the available receptors.
Affinity is sometimes expressed as log IC50, but it should state that somewhere. It's really not correct to use that definition, as it embeds receptor response characteristics in the definition.
>So a high number means that a LOT of the substance is required to bind to 50% of the receptors or something along those lines. Of course-this needs to be clarified a lot, I'm sure, but I think that *generally* that is somewhat true.
You're right. If a high concentration is needed to have a 50% effect, then the substance *probably* does not bind strongly to the receptor. However, this is a functional definition. There might be a high binding affinity, but there may be multiple binding sites, all of which need to be occupied, before the receptor function changes measurably.
>
> Thanks, Ritch. Your description helps me understand the relationship of higher numbers to lower affinity. - Appreciate that. : )
>
> -kotsunegaNow, back to the definition of affinity.
If affinity is expressed in terms of K(subscript)d, then you're talking about a standardized term for affinity. K(subscript)d is the ratio of two opposing effects, k(subscript)d (little k), which is the dissociation rate constant, i.e. the tendency of the ligand to release its bond with the receptor as a function of time, and k(subscript)a, the association rate constant, which is the tendency of the ligand to find the receptor in the first place.
k(subscript)a is largely determined by the molecular weight of the ligand; big molecules do not diffuse through solutions as well as small ones can. In practical terms, it is conceived of as a constant, and is sometimes ignored altogether.
k(subscript)d is determined by the ionic and other binding forces acting between the receptor and the ligand. Molecules are not rigid. They vibrate and twist around, and they are constantly being bumped by other molecules. If there's enough momentum at the right moment, the ligand molecule will leave the receptor. The rate at which that happens is k(subscript)d.
K(subscript)d (capital K), is sometimes, then, simplified as the inverse of k(subscript)d, or 1/k(subscript)d. k(subscript)d has units of molecules/sec, so K(subscript)d has units of sec/molecule.
I hope that wasn't too geeky.
Lar
Posted by cybercafe on June 18, 2003, at 12:57:45
In reply to Re: receptor affinity » kotsunega, posted by Larry Hoover on June 18, 2003, at 9:39:43
this is a good post... dr. bob should put it in the FAQ
> > > > > > > Thanks, but I'm still confused a little. What exactly does high affinity mean? I thought it meant the degree of attraction to a specific receptor, but from your post, it sounds like I've got that wrong. Please explain if you can.
>
> Actually affinity is defined in terms of the likelihood of the ligand (the substance binding to the receptor) releasing itself from the receptor site. In other words, affinity is defined as the inverse of dissociation. I'll explain more fully in a moment.
>
> > > > > >
> > > > > > No, you've got it right.
> > > Ok-I read this a LONG time ago, but from what I remember the "numbers" that you see (with regard to "affinity") have to do indirectly with the number of molecules of a given substance it takes to bind to 50% of the receptors (I think outside the body in a dish-but it is close enough analog of what happens in the body that it is useful info).
>
> No, sorry. That's the IC50, or EC50. That's the concentration of a ligand which has the physiological effect of inhibiting or exciting 50% of the available receptors.
>
> Affinity is sometimes expressed as log IC50, but it should state that somewhere. It's really not correct to use that definition, as it embeds receptor response characteristics in the definition.
>
> >So a high number means that a LOT of the substance is required to bind to 50% of the receptors or something along those lines. Of course-this needs to be clarified a lot, I'm sure, but I think that *generally* that is somewhat true.
>
> You're right. If a high concentration is needed to have a 50% effect, then the substance *probably* does not bind strongly to the receptor. However, this is a functional definition. There might be a high binding affinity, but there may be multiple binding sites, all of which need to be occupied, before the receptor function changes measurably.
>
> >
> > Thanks, Ritch. Your description helps me understand the relationship of higher numbers to lower affinity. - Appreciate that. : )
> >
> > -kotsunega
>
> Now, back to the definition of affinity.
>
> If affinity is expressed in terms of K(subscript)d, then you're talking about a standardized term for affinity. K(subscript)d is the ratio of two opposing effects, k(subscript)d (little k), which is the dissociation rate constant, i.e. the tendency of the ligand to release its bond with the receptor as a function of time, and k(subscript)a, the association rate constant, which is the tendency of the ligand to find the receptor in the first place.
>
> k(subscript)a is largely determined by the molecular weight of the ligand; big molecules do not diffuse through solutions as well as small ones can. In practical terms, it is conceived of as a constant, and is sometimes ignored altogether.
>
> k(subscript)d is determined by the ionic and other binding forces acting between the receptor and the ligand. Molecules are not rigid. They vibrate and twist around, and they are constantly being bumped by other molecules. If there's enough momentum at the right moment, the ligand molecule will leave the receptor. The rate at which that happens is k(subscript)d.
>
> K(subscript)d (capital K), is sometimes, then, simplified as the inverse of k(subscript)d, or 1/k(subscript)d. k(subscript)d has units of molecules/sec, so K(subscript)d has units of sec/molecule.
>
> I hope that wasn't too geeky.
>
> Lar
>
>
Posted by Larry Hoover on June 18, 2003, at 13:53:55
In reply to Re: receptor affinity » kotsunega, posted by Larry Hoover on June 18, 2003, at 9:39:43
> > > Ok-I read this a LONG time ago, but from what I remember the "numbers" that you see (with regard to "affinity") have to do indirectly with the number of molecules of a given substance it takes to bind to 50% of the receptors (I think outside the body in a dish-but it is close enough analog of what happens in the body that it is useful info).
>
> No, sorry. That's the IC50, or EC50. That's the concentration of a ligand which has the physiological effect of inhibiting or exciting 50% of the available receptors.There is a commonly used definition of Kd that is in molar units (concentration), simply the concentration at which 50% of the receptor sites are occupied.
See: http://biosci.usc.edu/courses/2001-spring/documents/bisc411-handout24.pdf
> If affinity is expressed in terms of K(subscript)d, then you're talking about a standardized term for affinity. K(subscript)d is the ratio of two opposing effects, k(subscript)d (little k), which is the dissociation rate constant, i.e. the tendency of the ligand to release its bond with the receptor as a function of time, and k(subscript)a, the association rate constant, which is the tendency of the ligand to find the receptor in the first place.This definition is supported by:
http://www.nanomedicine.com/NMI/3.5.2.htmIt seems my brain filtered out the volume term in my definition of Kd, so it is possible there is some commonality in the definitions, but the latter one involves time (rate), so there are differences, too.
Damn, I hate it when scientists can't "keep it simple".
Lar
Posted by Larry Hoover on June 18, 2003, at 14:15:20
In reply to Re: receptor affinity (two definitions..Aarghh!), posted by Larry Hoover on June 18, 2003, at 13:53:55
>
> > > > Ok-I read this a LONG time ago, but from what I remember the "numbers" that you see (with regard to "affinity") have to do indirectly with the number of molecules of a given substance it takes to bind to 50% of the receptors (I think outside the body in a dish-but it is close enough analog of what happens in the body that it is useful info).
> >
> > No, sorry. That's the IC50, or EC50. That's the concentration of a ligand which has the physiological effect of inhibiting or exciting 50% of the available receptors.
>
> There is a commonly used definition of Kd that is in molar units (concentration), simply the concentration at which 50% of the receptor sites are occupied.
>
> See: http://biosci.usc.edu/courses/2001-spring/documents/bisc411-handout24.pdfUnder this definition, affinity increases as Kd *decreases* (negative correlation). And, Kd would have values such as "6.2 x 10(superscript)-8 M", or units in micromolar (10 exp. -6 M), nanomolar (10 exp. -9 M), even picomolar (10 exp. -12 M).
> > If affinity is expressed in terms of K(subscript)d, then you're talking about a standardized term for affinity. K(subscript)d is the ratio of two opposing effects, k(subscript)d (little k), which is the dissociation rate constant, i.e. the tendency of the ligand to release its bond with the receptor as a function of time, and k(subscript)a, the association rate constant, which is the tendency of the ligand to find the receptor in the first place.
>
> This definition is supported by:
> http://www.nanomedicine.com/NMI/3.5.2.htm
>
> It seems my brain filtered out the volume term in my definition of Kd, so it is possible there is some commonality in the definitions, but the latter one involves time (rate), so there are differences, too.Under this definition, affinity increases as Kd *increases* (positive correlation). High affinity ligands would have lower kd values, so 1/kd would be relatively large. However, Kd under this definition could have values much smaller than, or much greater than, 1.
These two Kd's measure different things, and behave in opposite ways from each other. No friggin' wonder this is confusing.
:-/
Lar
Posted by Larry Hoover on June 18, 2003, at 18:24:07
In reply to Re: receptor affinity (two definitions..Aarghh!), posted by Larry Hoover on June 18, 2003, at 14:15:20
Posted by Ritch on June 19, 2003, at 11:20:25
In reply to Re: receptor affinity (two definitions..Aarghh!), posted by Larry Hoover on June 18, 2003, at 14:15:20
> >
> > > > > Ok-I read this a LONG time ago, but from what I remember the "numbers" that you see (with regard to "affinity") have to do indirectly with the number of molecules of a given substance it takes to bind to 50% of the receptors (I think outside the body in a dish-but it is close enough analog of what happens in the body that it is useful info).
> > >
> > > No, sorry. That's the IC50, or EC50. That's the concentration of a ligand which has the physiological effect of inhibiting or exciting 50% of the available receptors.
> >
> > There is a commonly used definition of Kd that is in molar units (concentration), simply the concentration at which 50% of the receptor sites are occupied.
> >
> > See: http://biosci.usc.edu/courses/2001-spring/documents/bisc411-handout24.pdf
>
> Under this definition, affinity increases as Kd *decreases* (negative correlation). And, Kd would have values such as "6.2 x 10(superscript)-8 M", or units in micromolar (10 exp. -6 M), nanomolar (10 exp. -9 M), even picomolar (10 exp. -12 M).
>
> > > If affinity is expressed in terms of K(subscript)d, then you're talking about a standardized term for affinity. K(subscript)d is the ratio of two opposing effects, k(subscript)d (little k), which is the dissociation rate constant, i.e. the tendency of the ligand to release its bond with the receptor as a function of time, and k(subscript)a, the association rate constant, which is the tendency of the ligand to find the receptor in the first place.
> >
> > This definition is supported by:
> > http://www.nanomedicine.com/NMI/3.5.2.htm
> >
> > It seems my brain filtered out the volume term in my definition of Kd, so it is possible there is some commonality in the definitions, but the latter one involves time (rate), so there are differences, too.
>
> Under this definition, affinity increases as Kd *increases* (positive correlation). High affinity ligands would have lower kd values, so 1/kd would be relatively large. However, Kd under this definition could have values much smaller than, or much greater than, 1.
>
> These two Kd's measure different things, and behave in opposite ways from each other. No friggin' wonder this is confusing.
>
> :-/
>
> Lar
Hi Larry, I had this feeling it had to do with "number of molecules" at bottom, or ultimately how easily one given molecule of the substance will bind to one receptor. Interesting stuff-wished I would have taken more than one chemistry class, though! I got panic attacks in those large college lecture halls-maybe it was the sinister looking sinks with the black chemical-resistant tops? ;)
This is the end of the thread.
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