Addicted to Chemistry

Making useful agents for studying substance abuse disorders.


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Sort of Like Mr. Smith Goes to Washington, but Different

Earlier this week, I had the pleasure of meeting our Lt. Governor, Rebecca Kleefish:

2017-02-07-cuw-opioid-talk

Our key goal for this meeting was to engage in a dialogue with the state on what we are doing at CUWSOP to help train and inform the next generation of pharmacists and health care providers. For my part, I discussed our efforts on developing a new, non-addicting analgesic (stay tuned, sports fans!). One of the cool things to come out of Madison is the HOPE Agenda (Heroin, Opioid Prevention and Education). The recent efforts of Rep. Nygren have been to update the HOPE Agenda with legislation that recognizes the transition from licit to illicit opioid use. Of course, I made sure to mention that the best way to stop this transition is to develop opioids that are non-addicting in the first place! Here’s hoping 2017 brings us some good news on some of these NIH grants! screen-shot-2017-02-07-at-8-58-35-pm


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Seems like an omen

It’s Friday the 13th…page number 666…and a Cunningham lab publication! Truly something eerie going on in Mequon!

bmclI want to write just a little bit about this paper – and, to provide a teaser for something else cool I have cooking up! First, this is a publication that has been (literally) 10 years in the works. What took so long? Did it really take you a decade to make 3 compounds?

The idea actually had its origins in my graduate career. My Ph.D. advisor had a grant to study dual-acting opioids, or compounds that simultaneously engage mu and delta opioid receptors. I was not working on this project – after all, I had my OWN funding – but, when you hear about cool stuff going on in other corners of the lab, you start to get a little curious. So, I did a bit of literature review and saw that there was a compound called BNTX, which may or may not be a delta-selective antagonist. BNTX had structural similarity to some of the things I was working on, so I thought, hey, let’s dive a little deeper.

So after making a convincing argument that it was worth my time, I synthesized BNTX, and designed our initial analogue, BOM, for reasons that you can find in our paper (follow this link). I sent them to my in-house collaborator and also got them ready to go out with the next batch for pharmacologic testing. This all happened, eh, around Spring 2007.

When Summer 2007 came around, we got the data back on all the compounds we sent. When we got to BOM, we saw that it (sort of) fit the profile that we wanted! Great! It wasn’t all that potent, but we had plans for that (again, read the paper). I whipped up another batch for testing, and made a couple analogues to follow up, and left them on the boss’ desk. Where they sat. And sat. And sat. And (probably) got lost. And forgotten. Spring 2008.

Fall 2008 rolls around and I defend my Ph.D. I had made BOM and some other ring-constrained compounds, and basically had to say, “this is a work in progress” in a couple chapters. I leave for an awesome postdoc at KU, and then start an independent career in Wisconsin. I kept thinking about that series and what else I would do with it once we got all the data we needed. Well, in 2012 I found that we actually had mouse data! So, that means the boss had lost my old material and put a postdoc onto the task of re-making BOM, and ultimately testing it in vivo. Only took them 4 years, but who’s counting?

Fast forward a few more years and we get to where we are today: I needed to get some last pieces of data for this paper so I put a Pharm.D. to the task of re-making and purifying BOM, send it off for the final tests, and then we set out to start writing. All told, the writing process took only about a couple weeks (not counting periods of work-distraction), and the collaborative team works really well together.

So, sometimes science happens quickly, sometimes it doesn’t. Would I have liked to have gotten this paper out years ago, so we could be publishing all the other cool things we’ve wanted to do? Totally. But, good science is good science, and there are no medals for speeding through a project.


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On the subject of meetings

In yesterday’s post, I spoke a lot about attending the AAPS Annual Meeting. AAPS is a large organization; it is not a Very Large Meeting, like an ACS (13,000*) or SfN (30,000), but it still pulls a sizable crowd (7500).

*ACS, of course, holds two annual meetings, Spring and Fall, which average around 13K apiece, give or take.

2016-ecb-meeting-mcw-cwc1I also frequently attend smaller meetings: you can typically find me at the BBC meeting hosted by UTHSCSA Department of Pharmacology in San Antonio, TX, and I also attend the ICRS, INRC, and CPDD meetings when I can. Earlier this month, I attended a local meeting hosted by the Neuroscience Research Center down the road at MCW. As you can see at the left, I also was persuaded to chat about some of our recent findings.

Having now attended my fair share of conferences, large and small, I can pretty safely say that the two are vastly different ecosystems. So, what are the pros and cons? When you only have so much cash to spend every year, where do you spend it?

Let’s start with costs: smaller meetings are typically cheaper. That goes without saying; if you only need to reserve a single ballroom or two at a hotel, you can certainly pass up on the big convention center. Along those lines, smaller meetings are more flexible: there are only so many cities that have so many convention centers, so you pretty much have to have those future meetings planned into the next administration. Of course, if money is no object…

…you can start factoring in what goal(s) you are trying to accomplish by attending a conference. If your primary interest is networking, a bigger meeting will, by nature, have cwc-linz-acs-boston-2015more people with whom to network (networking happening at left, with Dr. Thomas H. Linz of Wayne State); however, you need to consider who those people are – and whether you will gain much by networking with them – before you decide to write off those smaller meetings. Case in point: I know that the BBC meeting will have roughly 150-200 attendees, two orders of magnitude less than SfN. The difference is that those 150 people are all intimately involved in drug abuse research: chemists, biologists, behavioral pharmacologists. I know the people I need to talk to are here at this meeting, and by sheer concentration, I am confident that I will find them over the course of 2 days. These are also the people that will be reviewing my grants, so it never hurts to make an introduction.

acs-boston-2015The same rationale applies when your goal is to gain new knowledge: larger meetings will have more sessions, symposia, roundtables, forums, posters, etc. In my experience, they also have more wizardry (at left is from ACS-Boston Fall 2015). One thing I have noticed is that the smaller meetings tend to have more late-breaking research; ICRS, for example, explicitly requests that results presented at the annual meeting be unpublished at the time of submission. Both large and small meetings have one thing in common: they both provide opportunities to learn a lot about different fields, and to help your research grow in new directions. Whichever you choose, remember this: you are the one that determines how much you get out of it, so you had better make the most of your time.


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‘Tis the Season for an Update

After chatting for a bit about chemistry with my good friend, Dr. Alex Grenning, it occurred to me that my social media presence is not being felt terribly well. So, in the spirit of making an early New Year’s resolution, I resolve to be more visible.

In recent weeks, I returned “home” to Lawrence, KS, to attend the GPEN 2016 meeting and re-stomp around old grounds of KU Med Chem. It was great to run into old friends and colleagues, and to see how things are chugging right along.

From Lawrenc2016-aaps-ku-tiee, I continued on to Denver, where I attended the AAPS 2016 Annual Meeting. I had quite the presence at the meeting this year. First of all, I had my phone with me. Which, of course, means selfies.

For those not in the know, AAPS (American Association of Pharmaceutical Sciences) is an organization that caters to pharmaceutical research and development. This largely follows industry trends – after all, academic hiring trends means that most pharmaceutical scientists anymore are in industry, not academia – but also has a few certain niche areas that can be filled by academics. In particular, one might note that industry tends to follow its own nose a bit, frequently distracted by the fads of the day. One thing we 2016-aaps-faahacademics can do is offer perspectives on industrial failures. As I have discussed here previously, there was an extremely tragic clinical trial disaster that occurred earlier in 2016. One response from industry was to call for an immediate suspension of clinical trials for FAAH inhibitors until further testing could confirm safety of other classes of FAAH inhibitors (a very smart thing!). Subsequently, the FDA completed these tests and concluded that the toxicities associated with BIA 10-2474 were ligand-specific, and not representative of the class as a whole. I organized a Hot Topic related to lessons to be learned from the BIAL disaster. It was well-attended, and sparked some interesting discussions.

2016-aaps-peptidesWe also organized a symposium related to peptide-based drug discovery and development. As a small-molecule chemist who deals mostly with brain-permeable alkaloids, peptides tend to discourage me: they tend to have solubility issues, they’re chewed up by peptidases, central bioavailability?? Forgettaboutit. What this symposium sought to do was introduce best practices in peptide-based drug discovery and development, and to clear up some of my, well, misconceptions about this field. I now have a better appreciation for peptide-based drugs, even if I never wind up making any, myself.

Finally – did I mention I actually spent time, you know, enjoying the meeting? – I was also part of the organization of another symposium related to modeling and simulation. Here, we introduced ways that molecular modeling can be applied to drug repurposing, or the use of an existing drug to treat a new disease or target a new protein. I was unable to actually attend this symposium because I was busy moderating my hot topic; but, I understand that there was a lot of engagement and discussion that happened between speakers and audience. Overall, a big success.

Our lab has been up to a lot lately: graduated one technician to greener pastures, welcomed the next to our family, published the first (of hopefully many!) paper on potentially non-addicting opioids, and even gave a seminar at a local endocannabinoid pharmacology conference. Look for those topics to come down the pike in the near future.

 


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Colorful Chemistry: Part 1

Happy Tuesday!

I thought I would share a series of photos from last week, where I had occasion to convert a pyridyl ketone into an oxime.

reaction 2

When I first added hydroxylamine hydrochloride to the flask, I noted that the clear solution immediately took on a pinkish hue. We are stirring on ice just to be safe.

After about 15 minutes, I checked back on the flask and noticed that the color had changed from pink to a dark orange, maybe the color of pulpy orange juice. You can see that at the right.reaction 3

These first two color changes both took place at temperature around 0-5C. Of course, it is not uncommon for colors to change as a reaction proceeds to product. I wondered whether this would be the color of our pyridyl oxime product; I took the reaction out of the bath, and let it stir at room temperature to complete the conversion.

reaction 4

At left is the final color change as product formed. What once was pink, then orange, now took on a salmon color; I suspect this is the result of the reaction “splitting the difference,” and having the dark orange offset by the light pink. This is all pre-workup, too, so there is aqueous HCl and triethylamine floating around in there (we went with NEt3 over pyridine to aid the workup). Pyridine is not your typical tertiary base in many respects. So, the “fireworks” that we see here is not necessarily unexpected, but it cool to note anyway.

 


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Summer has started!

Another semester down, infinite more to go. Hopefully, the future will not include (m)any more semesters like I just had (coordinator of 3 courses, teaching in a 4th, and day-to-day fires to extinguish).

With this post, we head into the summer. I have an awesome team of around 8 Pharm.D.’s and undergrads who are working on some projects with me and others in our group, in synthetic organic chemistry, molecular modeling, and also in vivo pharmacology. My fantastic technician, Rachel, just took a position at MCW, which we are also excited about.

20160603_134949To kick things off, here is a shot of our first purified product that is ready to ship out this week. We found a new set of conditions that affords us a Knoevenagel condensation, and, perhaps more crucially, we found a solvent system that lets us purify the spots shown here. That took a little luck, actually; those two spots were stubbornly on top of each other until we landed here, and crystallization/salt formation was giving us fits. Now that we have conditions down, we are ready to rock and/or roll! Keep looking here for updates.