Good morning
On behalf of the Department of BioMolecular Sciences,
the School of Pharmacy and the University of Mississippi,
we are pleased to have you here today for our 2019 Coy W. Waller Distinguished Lecture.
We are thrilled to have Dr. Laura Bohn of The Scripps Institute as our speaker.
You will hear more about her shortly from Dr. Sudeshna Roy.
Bur first Dean David Allen will open our program by sharing the history and significance of this lecture series.
After the lecture, we welcome questions from the audience.
We will have BMS graduate students available to provide you with a microphone
for your questions.
It is now my pleasure to welcome Dean David Allen.
[applause]
Thank you very much, Kristie. Well good morning, everyone!
I'm so pleased to see everyone here
today as we honor Dr. Coy W. Waller.
I’d also like to thank the Department of BioMolecular Sciences for co-hosting this event
as well as Dr. Laura Bohn for serving as our 2019 Waller lecturer.
It is my great privilege each year to tell you a little
bit about Dr. Coy W. Waller,
an amazing man with a truly incredible
legacy in natural products research this
This is the 16th lecture we've held with
honorDr. Waller since 2004.
Dr. Waller was born in 1914 in North Carolina. He received his bachelor's degree in pharmacy from
the University of North Carolina, his
master's degree in microanalytical chemistry
from the University of Buffalo and 
and his doctorate in pharmaceutical chemistry
the chemistry from the University of
Minnesota. In 1968 he began his 11-year tenure
at the University of Mississippi
and the associate director of the
Research Institute for Pharmaceutical
Sciences, and in 1970, he became the Institute's first full-time director.
He advanced the institute in immeasurable ways.
His focus on natural products as a source of new pharmaceuticals
laid the foundation for our National Center for Natural Products Research
the first and largest of the institute’s now four centers
and the only such institute that exists on a university campus.
Before he retired in 1979,
Dr. Waller conducted research on poison ivy and on the use of cannabinoids to treat glaucoma.
He also helped edit bibliographies on marijuana and cocaine.
Over the course of his career, Dr. Waller
authored more than 50 patents
which were issued in over 150 countries.
He was passionate about inspiring students and young colleagues to pursue natural products
about helping them realize their potential to develop new pharmaceutical products.
In 1993 the university honored him by
dedicating the Coy W. Waller Laboratory Complex,
a natural products laboratory
that houses our marijuana garden
medicinal plant garden and greenhouses
Dr. Waller was one most accomplished scientists of his time.
When he passed on April 24, 1998, he left a legacy of leadership and research excellence.
We are incredibly grateful for his contributions to our school, our nation and our world.
We are honored to have some of Dr. Waller's family with us today.
Ms. Deb Carnathan,  Ms. Liz Thomas and Ms. Ashley Couch.
Would Dr. Waller’s family please stand so that we may recognize you?
[applause]
We truly appreciate your  presence here today we're grateful for all that you and your family have done for our school,
for pharmacy and this great university.
I'd now like to introduce Dr. Sudeshna Roy, assistant professor of medicinal chemistry and pharmacognosy
She will introduce Dr. Bohn as our 2019 Coy W. Waller Distinguished Lecturer. Sudeshna?
Thank you, David.
It is my privilege and honor to introduce the 2019 Coy W. Waller Distinguished Lecturer, Dr. Laura M. Bohn.
Dr. Bohn is a professor of molecular medicine and neuroscience at The Scripps Research Institute in Jupiter, Florida.
She received her Bachelor of Arts in chemistry and Bachelor of Science in biochemistry
from Virginia Tech, before earning her PhD in biochemistry and molecular biology
from the St. Louis University School of
Medicine. She completed her postdoctoral
work and the Howard Hughes Medical
Institute at the Duke University Medical
Center in the laboratory of dr. mark
Karen in collaboration with the 2012
Nobel Prize winner in chemistry dr.
Robert Knepper is dr. bond was a tenured
associate professor of the Ohio State
University College of Medicine in the
department's of pharmacology and
psychiatry before she joined the Scripps
Research Institute in 2009 dr. Vaughn
has made significant contributions still
we are research and has published over
100 journal articles book chapters
reviews and patents
our work in bars licking signaling has
changed the way that many researchers
understand opioid pharmacology she think
to use to be a thought leader in this
field and is now extending the lessons
of bicycling from opioids to
cannabinoids in addition to the multiple
consulting roles she is an affiliate
member of the brain Institute and the
Florida Atlantic University among her
numerous professional recognitions are
the Young Investigator award from the
Society of neuroscience the Joseph
Watson Young Investigator award from the
College on problems of drug dependence
and the Victor mud lecturer from the
international regulatory peptide Society
she also received the John Jay Abel
award in pharmacology from the American
Society of pharmacology and experiment
of their appearance the department of
biomolecular sciences is honored to have
dr. Laura Vaughn with us today
Ashley presents a talk entitled refinery
will be artists after signaling to
improve the therapeutic potential please
join me in welcoming dr. Nora
it's beautiful okay so because
with all the pharmacy students later or
mechanisms so the g-protein coupled
receptors are seven transmembrane
spanning receptors are found on the
surface of cells also can be found
inside fill but their membrane
transmembrane receptors so they span the
membrane and why cancel mic to the
surface and transmit signal transduction
into the cell into the neuron cell body
what to do
so the opioid receptor new receptor but
also drugs that are very useful practice
we know from studies that knockout mouse
models that exception of these compounds
you no longer have the overdose you no
longer have the respiratory suppression
the constipation or the abuse liability
so this receptor is really integral to
all of the effects one it cost
suppression codeine it's an anti
also overdose as well as constipation
tolerance that we develop over time
physically dependence to where you
become reliant on the compound to not go
through withdrawal and also addiction
reporting problems so great drugs
working some great useful drug it would
if you've ever had surgery you'd notice
do we need the system well we also know
what we see here is that this has been a
real problem the context tracks really
to a lot of marketing
so as we as we see over time - whoa you
can see that around 2010 we started to
see a rise in heroin and then more
recently we've seen an influx of
synthetic opiates and that would be
professionals that are coming in
directly so this has been a huge problem
I know when I was in Ohio but so many
people were using until they started to
restrict and then that wasn't like and
uh we always the first to do it and then
there was Florida and as they started to
implement the restrictions of pharmacy
prescribing a government prescribing and
tracking the privacy prescriptions
across different proxy statement just
shot their prescriptions around and get
10 bill well they saw you know we're
going to drop in prescription abuse
that 2010 start to see the heroin
overdose because subway oxycontin which
was very cheap to buy on the street
became very hard together and heroin
started taking place and then parents
quality also very high and then of
course so that's where we are and so to
try to fix this over this epidemic and
so there are initiatives to develop new
kinds of drugs
I'm going to talk to you today about the
receptor which is a drug we know
morphine for very long time we know how
to use it clinically we know either the
right conditions and situations it's
actually a very useful drug and we're
using that our understanding of you'll
do it yourself think about how those new
kind of compounds are safer and might be
useful okay so I'm just going to break
this down
and these are expressed on the surface
of neurons and that would drug binds it
pleads to the interaction of
intracellular effectors so it's almost
surface it's going to be the blood if
it's the receptor and it turns out in
there on those number things but this
concert of assembling things that you
say we're signaling complexes act
together to tell the neuron what to do
in pain pathways it suppresses fire and
says don't sense this pain that's what
what we want to preserve but these
receptors are expressed as many
different types of neurons throughout
the brain and they're expressed around
the body so the same receptor event and
it's engaging in the brain and saying oh
maybe ap perception is also engaging the
enteric nervous system and saying no
water secretion same drug is living the
same receptor in the brain stem regions
that control respiratory function and so
we're looking for a way to realign now
you could take an approach like ammonium
was great but when you have multiple
effects that are associated in different
regions of the brain it's really hard to
try to get the drug to just go to the
receptor they didn't want so we start
thinking about this differently and
instead of thinking about just an
antagonist so morphine's an agonist
well in this and that's the selectivity
but we know also that an antagonist and
then attacks maybe just subtly different
chemical structure than the agonist
so when we think about these things but
what I'd like to introduce you to is
that there's one protein in one region
this is what we're the ligands
the receptors for these Jupe staircases
but they act as orient approaches
the VRS is facilitated and once their
seventy's internalized if they still
signal which allows for compartments
like securely isolating a signal or it
may be too big relation or it may lead
to recycle so you see if there is
differentially it's a pivotal point of
separating a multiple array of signals
that we could even preserve and that's
why we like to look at it I will remind
you that in addition to just GG proteins
we always make the opioid receptors and
Gi couple protein more than GI 1-2-3 the
GTO the GGC
it'll signal to those as well and
there's many different proteins and the
expression varies throughout the body
and different now and the different
types of - protein as well there's the
the alpha subunits and then there's the
beta gamma and it might be a little
different we look at outputs but those
would always prefer that
but biology has done that for us and we
don't even really fully appreciate those
interactions all opportunities for
refining therapeutics this is very
complicated and crowded but I only want
to bring home the point that this is a
synapse and this is showing just the
number of proteins that this author
wanted to talk about was paper a synapse
is a very structurally defined area
where there are transmitters are
released and more receptors are highly
populated and the proteins that are
there in a synapse are even present in
the soma or the dendrite or other parts
of the cell so this becomes another
question will the receptor signal in the
same way in a summer versus a similar
many opportunities for proteins protein
interactions and for protein beta
residents that you very differently
modifying response so this is instead of
that linear simplistic model this is my
chaotic place what really does it you
know it's a wonder we have any drugs
at work because all of this isn't
happening all the time everywhere but
there's the possibility if it's ever
been shown to be able to interact it
possibly could be signaling a certain
way in a certain tissue and so our job
is in pharmaceutical development is to
figure out how we can target one path or
the pathway that we want that correlates
with a therapeutic benefit and to avoid
a pathway that correlates with an
adverse event and that's the challenge
using cell based assay systems and
models and trying to make this
correlation unfortunate because an
opioid receptor pharmacology especially
the fuel theaters of the pharmacology
that the translate ability is quite
polluted with these models I'm going to
talk about as far as the dose of
prediction human studies and so forth
these models are not necessarily models
of pain that are okay so here's how we
start I just told you that the body is
liquid complex and there may be an
opportunity to have good signaling and
avoid bad but what is good signaling and
once
signaling and I'd say about eight years
ago I was doing the rounds the number of
pharmaceutical companies and they bring
me amazing which by signaling assays do
we problem let's say well what signaling
pathway is mediating your therapeutic
response that which is mediating your
adverse event and that's the big black
box that's think what we really fail to
know and I think it's because we all
started transfecting receptors and AG
keep cells studying the signal that
would be used to see rather than studied
in acceptor in these endogenous plays
and really developing regardless so this
is how we started for the mule really
receptors we started with genetic models
arrested too and we use the mouse model
that's been used for 100 years for
analgesic responses to the morphine and
its derivatives and we use those same
tests
what changes the other approach that you
can think is you could take your
assistant reset your system pick two
pathways define develop life into the
fact that they want and not the other
and then give it to the animal and the
conventional models that is known to be
mediated by your receptor and see the
different so the opioid receptor system
is great for this because most every one
of the side effects that new awareness
of their agonist have in humans
recapitulated in the mouth great diverse
physiologies okay so the first study was
was 20 years ago they arrested two
knockout mice we gave him morphine and
they had an enhanced response so this is
a hotplate test i'm going to use it
throughout the talk basically the higher
the number it means you give them the
drug you put it on more play-doh 55 52
degrees so it's not so far that's an
advantage so we put capital on ante
so down here at zero five second set up
at the hundred percent until twenty
seconds and so we measure each animal
for that and so we we found them working
work better if we took out they arrested
two and that really matches that first
hypothesis of how beta-arrestins work
think of the word the data arresting
it's a break itself resting statement
and so you can count the break
we then chronically treated those
animals and we gave them more means
daily and if you do that you will get a
shift at Coetzee
and that's tolerance so what used to
give you full well GCM and date one in
the open circles after nine days and
treatment it requires a lot more
we were surprised when we okay so where
the signal through the g-protein that we
keep that all going and
efficacious for trading painting maybe
not developed tolerance maybe not have
respiratory suggestions and the time we
were doing this this was in
collaboration with the company has a
clinical trial so what they did what we
have done is develop compounds that
stimuli and we publish this work in 2017
for the
development development plays well
little clinic speak a straightforward
synthesis he's a scalability very nice
easy to work with compounds great little
generate quite a bit in the lab
everything I'm going to go through
quickly but we've run a lot of controls
we're not my spare controls it's been
run heard the psychoactive drug
screening program from off target and
NIDA has now run it through their
medical development branch to that's
important the final some property of it
that gives a difference in physiology
based on by assimilating one receptor
but if the compound needs another
receptor it causes a different effect
that we found our understanding so
that's why it's been very important I
don't show it but we really make sure
the compounds are selected I'm going to
talk about why status I'm I'm just going
to briefly introduce this topic so when
I look at this and we're going to study
how a compound will activate a g-protein
cufflink versus an arrest in Kathleen
it's going to be a bunch of selfies guys
experiencing a lot of money regressions
it's very important to be your drug
development your essay
research activity relationship for
chemistry that you know a parameter that
you're going to uniformly trust between
all of your ethics but this is a
campaign we've been doing for nine years
and so these different people come in
and different people run the acetate and
so the essays have to be stringent and
Anthony control and in order to compare
the effective 1/2 C versus another acid
we utilize what's called the operational
model which was proposed by black and
left receptor occupancy versus activity
to understand how the receptor signals
in one way relative to a reference so
another compound and then we compared to
how the same compound of performs in
another they also relative to another
compound and in that way we're able to
normalize its individual effect between
the two pathways and then they compared
to otherwise you can't make repairs
and they use the example that in Chaplin
or working and I say what's the quote
here for me what is the and your
question should be in what aspect and
what condition is that a patient or a
said of dog is it a cat is a mouse
monkey what what are we talking about
here and it's the same thing if you were
just walking and she began a spy NSA and
it shows so much transfected you're
gonna get up quotes you around 30 animal
and if you were to test that same drug
in the same app that you're using a
brainstem measuring you're gonna get
about 200 nano moment policy so if I
were to say well those are two different
assays look it's an animal or coatsy
hearings 200 animal or coatsy here
changing so what we do is we take a drug
in this case the reference agonist we
use and we use it to the finest system
and so damn go here gives a full
response in our assay this is a gtp game
is 35 binding acid and it gives the full
response and here's one thing compared
to it and its policies about to hold
shift over here we have a beta arrest in
recruitment a state this is an enzyme
fragment complementation that means part
of the fiveaces on the receptor parts on
the roof on the beta rest and they come
together not even insulated you a lot of
reagent the students love it's quick and
it's treatable well in tons of data but
that's how morning lows and in the old
days when people started doing these
experiments it's all more think about
monogamy so it's different
Portia the policy shift is similar this
essay picks up partiality a lot more
than that ask me if you did this and
bring more pain with book just like this
it would be very partial where there's
not as many extra receptors we did this
comparison and we applied this modeling
to say here morphine was balanced it was
not showing - now I put a brand
associate ten different ways and I could
pick the different common reference and
I continue looking vital because it
biased number just like potency will
change because bias what is bias bias is
a comparative term thank it's not at all
hindsight's creates more requests of
this and so you change what you with
reference or you change the system and
biases wording so there's no absolute so
that was one of the first challenges we
did with this and we implemented this
stringently because we already believe
more things a good molecule and we want
to be better than watching I'll just
show you briefly buprenorphine this is
another one you can or thinks a partial
on the boat
as number spots we can't even calculate
bias so therefore and ultimately by its
distance streamlines but we we know as a
partial agonist for partial agonist will
inhibit a full agonist down to the right
so you can use that property it's
demonstrated here that g-protein on top
that if you put the buprenorphine
against down in the investment assay now
we can actually capture a functional
affinity of buprenorphine for our beta
rest and not accept that receive
actually has quite good affinity and we
feel that perhaps a body bag shouldn't
have functional affinity for the
receptor coupled to the beta resident
and so in our hands
okay so that's my big spiel on why I
think it's important to understand that
because it's all across GBC or
ecology and heritage development it's
it's very popular
so vice factors not a magic number it's
a number that you calculated face the
way you use this your essays and once
you use this your reference and all of
their conditions and in most cases
people don't even take into
consideration kinetic which I think the
new way it would we're really thinking
about this because kinetics can mask all
of this and make something with biased
when it's not so keep it in mind and
changing the they're changing the
reality this was important for us
because we're working in structure
activity relationships right we're
starting with a few compounds we're
gonna build many many compounds in this
group and we're gonna do prepared from
these are the compounds I'm going to
talk about so we have this eight hundred
sama compound collection that we
characterized and that you know at some
point you have to stop and say what do
we want to go after physiologically we
have all these compounds so what we did
is we selected six compounds from the
collection that spam bias some that
preferred data Reston and increasingly
preferring g-protein
and then we subjected them to full
analysis and being a good correlation so
this is what keep talking looks like on
top they're just graphed on different
different graph so you can see them
they're all good there and then and I'll
point out that curves are twice and
they're not hiding perfect because if we
put it against and go those in this
place so they really have very low
functional affinity for beta arrestin
valuable receptor we calculate then ec
fifties we calculate the taxes and we
calculate the bias the Delta Tau over ka
it's really the thing to take home here
is that we have this gradient of
compounds or morphemes right there in
the middle and the ones I'm going to
talk about the most of the arrows what
morphine has an arrow okay we did a lot
of controls I fell through them we
checked everything in the discovery
phase was all against the human
hasn't shorter at the terminus so we ran
everything advice to in most receptors
and also the accessories at orthogonal
screen we did all of it reading paper
and we did all the knockout by swings of
the steps of pharmacokinetics weak
stability the reason we do the key thing
is because I'm gonna take a compound on
the characteristic cell based assays I'm
gonna give it to a mouse I'm gonna say
do you one who same this morphine but if
my compound metabolized in ten minutes
of course it won't produce the effects
that won't beat it right so we have to
make sure it also got it to the brain it
has a very nice class not just
distribution lasts for quite a while has
very high capacity but it gets into the
brain and six to twelve so I'm just
going to show you some behavior data
this is that same hot place before and
so this is all showing different doses
but the maximum efficacy goes for each
of these compounds it all they all
produce interception and then we took
them into a mouse pulse oximetry so this
is just a symmetry
- saturation of arterial blood and
dramatic it's clear - which
we then can calculate a therapeutic
window by calculating the IDI 50 of both
responses and that's shown here and I'll
just quickly show you that here's how
the fifties work and this is the
therapeutic window so we take the 85th
bfpo - so we notice that this was of
course correlating with the bias factor
so he did a correlation analysis of G
protein versus arrested and respiratory
Arrangements exceptional we have a very
nice correlation and that's really the
best we can do at this point - no these
are as they are are are cell based
assays helping us pick the right
compounds that will wipe over separation
between antennas inception in
respiratory suppression unchecked
because a pretty good goal we also found
that our data that if we took the bait
arrested for three compounds and looked
at those individually had a nearly
perfect correlation with having a very
narrow therapeutic window
so I think that's an important thing to
consider too I will also point out that
just because it has a bias factor of 30
these two have a similar bias factor it
doesn't mean that that's going to be
devoid of the side effect
okay I've shown you the range in what
sometimes gets lost in that comparison
is that even though the compounds that
showed a lot of bias they still produce
respiratory suppression still here so
these are this compound over here in the
4960 oh thanks for cake and the other 15
and I mean it's very close to walking
around evenings for cake they were
actually very similar so potency and
efficacy will still matter and if you
it's not expected to be completely
devoid of side-effects right because if
we think about this protein interaction
it's all just coming it's just
overcoming to have an interaction Y
compliance it has a nice thermodynamic
can interact I've been buying less
energy put into the system so maybe it
doesn't but I'm not getting a little
waxing poetic so I'm gonna show you some
data that just got published it's just
been accepted and this is looking at
tolerance so I showed you who
chronically gave the compound so I just
want to talk about some new data so this
is a test we ran into a problem and
anybody here doing delivery and will
recognize this problem that our compound
was not soluble for repeated IP dosing
so we're a high schooler we always
measure the PK we always draw blood to
make sure our chronic goes in there
keeping our drug steady-state
tolerance well usually this was nothing
so we did first met cross feet and
looked at we saw those comments falling
out of solution and white color so
anybody this formulation will appreciate
this we tried many different ways to
overcome this but you know you make a
compound it turns out to have a 70% by
old oral bioavailability you don't mess
with the chemistry because this compound
actually did turn out to be very orally
bioavailable and this is shown up here
at those verses and my P dose beautiful
and so we get a similar in d50 so we
decided to go to an oral dosing
procedure pretty
17:18 compound here we did the PK this
is a vit distinct paradigm where we
treated them every day every 12 hours
without the dose so they were getting
point if they were getting 48 these
particular day or getting 24 in the
morning 24 in the evening we did that
per seven days and we measured lecture
halls at 2 6 and 12 hours after those
three days of compound delivery morphine
about 14% and so it's best to get
working by
here we all see code on though is orally
Lionel so we used it as a side control
in gated and the same exact way that we
gave the 1780 a total of 24 minutes for
Katie you can see in comparison to get a
lot less oxycodone available and it's
been found wage that you do 17 18 so
keep that in mind we're going to hammer
our system with these animals and show
very high concentrations over several
days much higher than what you've seen
for thoughts of code on unworthy and
asked do they develop tolerance so this
is morphine accomplices 1200 dinner and
announcement twelve and twenty four
forty an expert aid to get two and four
full shift in tolerance for oxycodone
adjusted 24 minutes per Pig VIP in
potency this is seventeen and I should
they do reach that's very little shift
in their aunt Atossa said the potency
and in fact it was a again a 1.3 full
shift which I thought was funny because
that's what we saw in the beta residence
you knockout mice so have oxycodone
there and that's show you the shift in
potency at each of the doses so we will
really resistant to develop a tolerance
in this backstage which i think is cool
we've ended the study where we took out
the hall
and we stopped dosing and we started by
turning the drawer so when you
chronically treat the mouse with an
opiate you take away the job they go
through signs of withdrawal and
essentially there it obvious everything
I should mention is extremely de lined
it it takes about five people to do all
the different kind of winding the dosing
and scoring so nobody knows what they're
looking at and we always try to stay
lean or vehicle control on the side so
what we we are encouraged
we don't know if this is a properly
biased agonism we actually think that
this is a benefit of our speaking
Russian so there is dependence we looked
at cross tolerance and if we probably if
we treat with the SR compound and then
treat it working so that we have these
lights that we chronically treated with
morphine and we gave us our so what
happens the next day so that was that's
the course the 50% point over here that
they that one hour that's the first test
it's okay to 50% responsive and then we
submit stated it gave them again they
seem to be getting a little more
responsive and the second than by a 48
hours we restored responsiveness well
that's weird
we're showing here buprenorphine in the
same type of setup these are working
tolerance we start getting very little
Dorothy not really their music does it
for a couple days nothing got better so
then we said what about it for three
full days of doing this and then we
challenged them again with morphine and
what was really surprising here or
wasn't surprising for buprenorphine of
the orange because that the animals have
had morphine and were working cholera
and we substituted that you preneur feet
they were still tolerant morphine I
don't think that's a surprise but when
we gave me a spark off of three days
they restored their potency the morphine
and that I think is the surprise I think
that's very unusual that an agonist
could come in and interact with the
receptor and actually restore its
responsiveness to after so this was it's
very exciting for us and we also found
in our control study where we've had the
vehicle treated saline Thompson and we
gave them buprenorphine for three days
that was enough to induce robust
tolerance so buprenorphine
is currently opportunity that we can
pursue and responsiveness to morphine
what was nice about those animals is
once when we did this study again and
this time during those three days that
we were
to suppress or to read and state the
working sensitivity
it was only resetting the pain
perception but it was suppressing the
withdrawal which is what you'd expect
the normal opiate to do that the don't
give the north the rotational therapy
will suppress the job so we think that
there's potential in drug development
for compounds of this class we're
actively looking at the molecular
pharmacology to try to understand what
is it join to the receptor the paper has
a little bit more biochemistry in it
were actively looking at this Center for
brain regions and neuronal population to
see what is it doing to stabilize that
g-protein signaling state and is that
what's really leading to this revived
receptor system so my thought the season
conclusion is going forward that
receptors can signal differently and be
differently regulated and context
dependent manner and that we can
hopefully take an opportunity to develop
therapeutics that will broaden our
ability to treat disease without side
effects it's not bias it's not
independent of hopes be the best we can
hope for I think is a white oak
therapeutic window not at all or not
it's not going to be magically we get
rid of it all the side effects but
hopefully we can refine them therapeutic
and I think that maybe we can
I think that holds tremendous potential
so I've showed you all this I showed you
we started our whole drug screen with
g-protein versus beta arrestin and I
showed you be arrested to knockout mice
didn't have some of these side-effects
but I haven't shown you the beta rest of
those any of those side effects in vivo
and that's where you guys are next
generation coming work on these things
because it's really hard to show this
signaling is in the endogenous setting
all the regions that regulate each of
these side effects and and pain
responses but this is our current
hypothesis but it could just as well be
a ton of protein without even thinking
about because even though they're SS
being all the same
so showing my lab this was taken
recently we have a very good group of
people that operate their lab coats
because the Institute was taking this
picture to show how good we are we all
have our safety glasses on so yeah we
were doing everything we should be so
the work I've talked about today was
spearheaded by Colin Schmidt she's
really organized everything she had been
a graduate student with me not a picture
because she's gone off the biogenic she
hasn't really made that she stayed with
me as a postdoc she did her PhD in
serotonin receptors by signaling and
then we switched her so she had Mormon
industry experience because she wanted
to go into industry Travis grim who's
not in the pictures he just left he went
to a farm up in Cambridge he could over
spearheaded the tolerance studies would
fan even fully this year
and we continued to do studies and you
don't really feel the pathways of course
abuse liability so forth and we have an
entire program on capital receptors
which I did not show
and of course we have a cannabinoid
program that will just pitch that
postdoc openings like graduate student
openings we're trying to work there we
take more of a structure function
crystal structure premium structure
predictive chemistry to try to model and
I think our first shot of selectivity
professor Bowen has a fabulous the story
is complicated not with respect to by
signaling when you throw in receptor
selectivity and capacitive drug
molecules to interact with other gpcrs
is particularly more feet where it's
Taba lies themselves one in particular
has its own sets of energies of problems
can you comment on that
thank you yeah it's funny because I just
got a night of us enamine working six
booth here on morphine three goofy bleep
you're on that that's important because
the bow spells and even think six book
behind which is the very low power so
we've actually just started putting that
in
it's very important I think also the
cannabinoids that's what we're really
running into the big question it's just
give me something some left if I can't
take care of Ebola so I know I can't
yeah yeah absolutely selectivity right I
think in the aisle so it's a little bit
more
and maybe the allosteric modulation
shuttling it more for one pathway or
another
and you're saying there's a particular
tool engaging in one way or another sort
of opportunity
so choking to our appreciation
you
