Smarten up

Assistant professor Ganesh Thakur's research could lead to a drug that has the cognitive benefits of nicotine without its negative side effects. Photo via Thinkstock.

Assis­tant pro­fessor Ganesh Thakur’s research could lead to a drug that has the cog­ni­tive ben­e­fits of nico­tine without its neg­a­tive side effects. Photo via Thinkstock.

Here’s a simple expla­na­tion for how many addic­tions work: you con­sume a chem­ical compound–through inges­tion, inhala­tion, whatever–that looks or works a lot like another com­pound that’s nat­u­rally present in your body. The nat­u­rally occur­ring, or “endoge­nous,” com­pound hap­pens to be one that binds to their spe­cific receptor in your brain that trig­gers a whole down­stream slew of events, such as increase in dopamine levels, that give you some kind of happy feeling, which you want to have again and again.

With nico­tine, the story is a little different…or at least a little more nuanced. Yes, there’s the pri­mary addiction-​​promoting receptor (it’s called α4β2 nico­tinic acetyl­choline receptor, or nAChR), but another receptor (α7 nAChR) also plays a role. This is the receptor that is respon­sible for the cog­ni­tion enhancing effects that one expe­ri­ences when they smoke cig­a­rettes (Really? Cig­a­rettes make us smarter? You betcha.)

While the dose of smarts isn’t the most addic­tive part of nico­tine, it cer­tainly increases a person’s desire for more, said North­eastern assis­tant pro­fessor of phar­ma­ceu­tical sci­ences Ganesh Thakur. He’s working on devel­oping alter­na­tives to things like mar­i­juana (as dis­cussed in this news@Northesatern story) and nico­tine that have the same ben­e­fits without the neg­a­tive side effects.

In one project, he and his team have cre­ated a com­pound that they’ve shown to be neu­ro­pro­tec­tive in animal studies: Older ani­mals that had already demon­strated dimin­ished cog­ni­tive capacity expe­ri­enced improved memory and cog­ni­tion when they took Thakur’s drug.

The drug works roughly the same way as other drugs he’s devel­oping to more safely reap the ben­e­fits of the mar­i­juana happy-​​making receptor, CB1. There, the idea is to target other recep­tors remote to the one of interest. Doing so, he explained, can either pro­mote or diminish the pri­mary receptor’s inter­ac­tion with the endoge­nous com­pounds. So, his marijuana-​​like drugs bind to a remote receptor and sub­se­quently cause CB1 to bind endocannabinoids–which are like nat­u­rally occur­ring THC molecules–in either greater or smaller amounts. The result are drugs that can treat things like anorexia ner­vosa (by pro­moting the desire to eat), obe­sity (by depressing that desire), glau­coma (by decreasing intraoc­ular pres­sure) and PTSD (by pro­moting the blissful feeling that comes with smoking dope), without the neg­a­tive side effects of addic­tion and impaired memory.

But in his work on the α7 receptor, he’s devel­oping an entirely new class of com­pounds that work a little dif­fer­ently. In the former examples–which are called PAMs (or NAMs), for pos­i­tive (or neg­a­tive) allosteric modulators–the process depends on a good supply of the endoge­nous compound.

Thakur is an assistant professor of pharmaceutical sciences and a faculty fellow in the Center for Drug Discovery. Photo by Brooks Canaday.

Thakur is an assis­tant pro­fessor of phar­ma­ceu­tical sci­ences and a fac­ulty fellow in the Center for Drug Dis­covery. Photo by Brooks Canaday.

But what if there is no endoge­nous com­pound, or there isn’t enough of it around to have much of an effect?

The new mol­e­cules Thakur is working on are called ago-​​PAMs. The “ago” stands for ago­nist, and it basi­cally refers to the fact that these com­pounds can pro­mote the ben­e­fits expe­ri­enced by binding of endoge­nous lig­ands to the pri­mary receptor without having to actu­ally do so. It binds to a remote (or “allosteric”) site on the receptor rather than the endoge­nous mol­e­cule binding site on α7, thus it’s still tech­ni­cally a PAM.

In a paper released on Valentine’s Day (fit­tingly, since Thakur is clearly in love with this sub­ject) in the Journal of Bio­log­ical Chem­istry, he and his team pre­sented a detailed account of the struc­ture of the allosteric binding site of α7 nico­tinic acetyl­choline receptor where such ago-​​PAM com­pounds sits on. This is impor­tant because without knowing what that pro­tein binding site looks like, it’s hard to make things that bind to it perfectly.

This finding,” said Thakur, “is going to help us develop more potent and effi­ca­cious com­pounds as memory and cog­ni­tion enhancers, addic­tion treat­ment, and for treat­ment of neu­ro­pathic pain.”

Indeed, he’s already had some promising results on the memory and cog­ni­tion front, thanks to a col­lab­o­ra­tive pilot research project with Jonghan Kim, a fellow assis­tant pro­fessor in the School of Pharmacy.