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.
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.