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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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May 16, 2012

Antidepressant Drugs and Cell Membranes

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Posted by Derek

How much do we really know about what small drug molecules do when they get into cells? Everyone involved in this sort of research wonders about this question, especially when it comes to toxicology. There's a new paper out in PLoS One that will cause you to think even harder.

The researchers (from Princeton) looked at the effects of the antidepressant sertraline, a serotonin reuptake inhibitor. They did a careful study in yeast cells on its effects, and that may have some of you raising your eyebrows already. That's because yeast doesn't even have a serotonin transporter. In a perfect pharmacological world, sertraline would do nothing at all in this system.

We don't live in that world. The group found that the drug does enter yeast cells, mostly by diffusion, with a bit of acceleration due to proton motive force and some reverse transport by efflux pumps. (This is worth considering in light of those discussions we were having here the other day about transport into cells). At equilibrium, most (85 to 90%) of the sertaline that makes it into a yeast cell is stuck to various membranes, mostly ones involved in vesicle formation, either through electrostatic forces or buried in the lipid bilayer. It's not setting off any receptors - there aren't any - so what happens when it's just hanging around in there?

More than you'd think, apparently. There's enough drug in there to make some of the membranes curve abnormally, which triggers a local autophagic response. (The paper has electron micrographs of funny-looking Golgi membranes and other organelles). This apparently accounts for the odd fact, noticed several years ago, that some serotonin reuptake inhibitors have antifungal activity. This probably applies to the whole class of cationic amphiphilic/amphipathic drug structures.

The big question is what happens in mammalian cells at normal doses of such compounds. These may well not be enough to cause membrane trouble, but there's already evidence to the contrary. A second big question is: does this effect account for some of the actual neurological effects of these drugs? And a third one is, how many other compounds are doing something similar? The more you look, the more you find. . .

Comments (25) + TrackBacks (0) | Category: Drug Assays | Pharmacokinetics | The Central Nervous System | Toxicology


COMMENTS

1. MLBpitcher on May 16, 2012 7:53 AM writes...

Congrats Derek Lowe for throwing a shutout against the Twins without striking anyone out.

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2. Kare on May 16, 2012 8:00 AM writes...

This result is also interesting given the unexplained influence of omega-3 fatty acids on cognition, behavior and mood. Presumably, membrane biophysics is playing a role there, as well.

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3. Innovorich on May 16, 2012 8:04 AM writes...

There were very similar results published several years ago for the effects of anesthetics acting via changes to membrane fluidity rather than (at least directly) through any particularly protein target.

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4. road on May 16, 2012 8:06 AM writes...

The other enantiomers of sertraline are apparently inactive, which suggests that the psychoactive effects of sertraline are not due to pysichochemical interactions with membranes. It's a pretty perfect control, IMHO.

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5. luysii on May 16, 2012 8:20 AM writes...

Ah, the antidepressants, we hardly know ye. For another example, this time with amitriptyline, a classic tricyclic antidepressant, and its possible use in cystic fibrosis, because it inhibits an enzyme involved in ceramide metabolism of all things see https://luysii.wordpress.com/2011/02/02/medicinal-chemists-do-you-know-where-your-drug-is-and-what-it-is-doing/.

It's post #13 in a series concerning how little we understand all the things our drugs are actually doing.

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6. PPedroso on May 16, 2012 8:21 AM writes...

I look forward to read Dr. Kell feedback on this.
Not from a negative we-were-right perspective but just to check how his team will incorporate this new data into their research since I see some direct implications with their line of thought.

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7. Curious Wavefunction on May 16, 2012 8:52 AM writes...

#4 road: Just a thought: Aren't phospholipids chiral? Could this result in the preferential interaction of only one sertraline stereoisomers?

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8. Anonymous on May 16, 2012 8:58 AM writes...

Did the mood of the yeast cells improve? Did they happen to make beer taste better afterwards?

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9. NoDrugsNoJobs on May 16, 2012 9:32 AM writes...

I think #4 makes a pretty good point. Correct me if I'm wrong but not only does the correct enantiomer have most or all of the in vivo effects but that in turn correlates with the binding affinity for the serotonin transporter. Having said that, clearly we don't know the downstream effects close to well at all. There is another antidepressant known as tianeptine which putatively promotes serotonin uptake - the opposite of an SSRI of sorts. What both tianeptine and SSRI's share is a tendency to grow the neurites in the hippocampus and prevent stress induced hippocampal shrinkage. Are there alternative mechanisms for the broader response - appears likely.

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10. Ethan Perlstein on May 16, 2012 10:37 AM writes...

Hi, I'm actually the corresponding author of the paper in question. In the spirit of Open Science, I encourage comments on my paper on the PLoS ONE website. As for this comment thread, if I may I'd like to chime in on the question of stereochemistry.

First, it's true that the enantiomer of sertraline has lower affinity (about 10-fold, but still submicromolar) for the serotonin transporter and is much less selective for the serotonin transporter, at least in synaptosomal assays. Please see the original paper on sertraline by the Pfizer scientists who developed it here: http://www.ncbi.nlm.nih.gov/pubmed?term=koe%20weissman%20welch%20browne. (Unfortunately it's behind a paywall). However, I'm not aware of data showing that sertraline's diastereomers are without behavioral effects in mice. But even if the diastereomers were without acute behavioral effects in mice, it would be interesting to see if the well-known physiological changes associated with chronic AD treatment in mice, e.g., BDNF expression, are also observed for the diastereomers.

Second, even though the enantiomer of sertraline is less potent and less selective for the serotonin transporter, it would still be predicted to accumulate in brain cells because it's lipophilicity is unchanged. The $64,000 question is whether sertraline is an antidepressant because of dual activities at hSERT and on cellular membrane homeostasis. That question could be teased apart synthetically by creating a less lipophilic sertraline analog that still possessed high potency and selectivity at hSERT, but I'm not aware of that experiment having been done either. If anyone wants to do the med chem, I'd be happy to test them in yeast and outsource the behavioral assays in mice!

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11. ZINC on May 16, 2012 10:59 AM writes...

@10 Ethan, there's usually no need to have some make a fresh compound. Especially in the case of known drugs, many people have made the compounds already and they are available for purchase, usually at prices academics can live with. For instance, here are the top 50 matching purchasable compounds of sertraline from ZINC:

http://zinc.docking.org/results/similar?structure.smiles=C%5BNH2%2B%5D%5BC%40H%5D1CC%5BC%40H%5D%28c2c1cccc2%29c3ccc%28c%28c3%29Cl%29Cl&structure.similarity=0.70

I'm sure with some clever searching you can narrow down the list to less lipophilic ones.

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12. ZINC on May 16, 2012 11:01 AM writes...

P.S. you may get lucky and find a less lipophilic one that also has potency for hSERT, since ChEMBL activity data is also imported into ZINC.

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14. lynn on May 16, 2012 12:47 PM writes...

Have they tested effects on bacteria, especially S. aureus and B. subtilis? It's amazing how many human health drug candidates [or at least compounds in industrial chemical libraries] kill bacteria via membrane interactions. However, these effects are often abrogated in the presence of human serum, usually due to the compound's binding to albumin.

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15. MoMo on May 16, 2012 5:23 PM writes...

Antidepressants do more than just anti-depress!

For fun I used to read all of CombinatoRx's patents, just to see how many times tricyclic antidepressants showed up as synergists in just about every disease known to man.

But Lynn knows the score here. Big lipophiles can change transport dynamics in all cells everywhere, and special old-school ones like Trifluoroperazine do all kinds of biological tricks. It causes orgasms during sneezes! Some side effect!

Somewhere someone is thinking-Where can I get some? ACCCHOOO!

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16. Fred on May 16, 2012 5:27 PM writes...

im with luysii. we just dont know what we are doing. I think membrane phase transitions are an overlooked and potentially important mechanism in drug action. I have read anesthetics work by altering the Tm of membranes and that you can revive an anesthetized person by placing them in a hyperbaric chamber and crankin it up. does anyone know if this is true?

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17. Ethan Perlstein on May 16, 2012 5:58 PM writes...

Thank you all for a lively and stimulating discussion thread. I wish this kind of exchange was happening on the comments thread of my paper on the PLoS ONE website. I reiterate my invitation bring some of this discussion directly to the paper here: http://www.plosone.org/article/comments/info%3Adoi%2F10.1371%2Fjournal.pone.0034024

Thanks!

-Ethan

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18. DJN on May 16, 2012 6:36 PM writes...

Not only antidepressants but beta-blockers have very unusual effects on red cell membranes. Crenellated cells arise and unusual pH changes occur within the cells. Found this out the hard way back in 1971 when looking for compounds that would shift the oxygenation curve of hemoglobin in vivo. DJN

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19. newnickname on May 17, 2012 7:05 AM writes...

@16: "anesthetics work by altering the Tm of membranes and that you can revive an anesthetized person by placing them in a hyperbaric chamber and crankin it up. does anyone know if this is true?"

If you replace "person" with "newt", "mouse" or other small animal, it is definitely true. See the work of KW Miller (Harvard), 1970s - 1980s. Put a mouse in a hyperbaric chamber on a slowly rotating (rolling) platform (drum) and the mouse has a reflex action to right itself. Apply the anesthetic and the mouse takes a snooze and rolls over and over as the platform (drum) rotates. Crank up the pressure with an inert gas (e.g., He) and the mouse wakes up and the righting reflex returns. Bring the pressure back down to one atmosphere and the mouse goes back to sleep. I don't remember for sure, but I don't think the pressures are too bad: 1000 psi? 1500 psi? ("tank pressure").

The closest human "experiments" I can think of would be the rescue of divers from Raptures of the Deep (nitrogen narcosis; the bends) by placing them in hyperbaric chambers. It works.

Small pressure cells ("bombs" to us chemists - I hope I didn't set off a Homeland Security alert by typing that) are easy to come by and can accommodate yeast more easily than mice.

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20. Cellbio on May 17, 2012 8:25 AM writes...

I am pleased to see work like this, as the pharmacological scheme most people imprint in their logic has limited experimental basis. What I mean is that we operate with the idea that a compound series can be well understood by biochemical and receptor screening panels, followed by in depth interrogation of the target biology without looking at "off target" biology until late in the game, like tox or clinical studies where we call them adverse events.

I have done this sort of broad screening in cell assays, and you see that with any collection of drugs or a series of highly related compounds against a target the data from Panlabs, Cerep or extensive target panels fails to explain the biological diversity of the compounds. Adding something akin to what these authors did, you can see that some compounds partition out of the media to membrane compartments, and equilibrate to the target from that compartment, while others remain in the media and are easily washed away. Some make the target invisible by flow cytometry, even though it is still there, some inhibit where others do not, some induce biological responses.

If ever you have the chance to screen hundreds or thousands of compounds that have depth of biochemical and receptor counter screen data across broad biological assays including things you do not expect, you will see clearly that empirical screening is the only way to fully understand the biological effects of a compound. Of course, with any luck, you do get to screen empirically, in tox or Ph1. But when you see that 100s to thousands of highly related compounds have impacts outside your "target" biology, entering clinical trials with no knowledge of these activities is quite foolish, in my opinion.

As for sertraline, I assume it was largely tested in behavioral assays, which would screen for optimal activity in vivo? If this compound was selected over others based upon superior performance in those studies, then I'd bet this profile of membrane partitioning does contribute to the pharmacology, if only influencing binding kinetics over dosing windows.

yes, the more we look, the more we find. i just don't understand why we do not look more than we do. The scheme or paradigm of discovery has failed, time for new approaches.

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21. g on May 17, 2012 9:17 AM writes...

Statins reduce infection rates and deaths by sepsis. Perhaps they decrease the viability of microbes through a similar mechanism.

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22. NJBiologist on May 17, 2012 11:22 AM writes...

@19--Nitrogen narcosis is an intoxication brought on by hyperbaric nitrogen. The bends is different; it's decompression sickness, brought on by bubbling of nitrogen out of tissue depots. Hyperbaric therapy elevates pressure and allows for slower, non-bubbling clearance of nitrogen.

Thanks for the pointer on the Miller studies; that's interesting work, and I wasn't aware of it.

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23. lynn on May 17, 2012 11:53 AM writes...

#21 - see for example: Jerwood, S., and J. Cohen. 2008. Unexpected antimicrobial effect of statins [which I also saw with mevacor in the late 80s]. Journal of Antimicrobial Chemotherapy 61:362-364. However, the mechanism of anti-Staph activity is unknown - and the doses in man are much too low to reach sufficient antibacterial levels [although the authors speculate on possible ways around that].

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24. newnickname on May 18, 2012 11:07 AM writes...

@22: Right. Sorry, I was sloppy. Raptures / narcosis occurs in the deeps. The bends can kill you on the way back up so a hyperbaric chamber can "squeeze" the nitrogen bubbles back into solution and allow for a slower, safer decompression.

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25. joeylawn on May 20, 2012 10:14 PM writes...

Interesting read. I take sertraline.

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