I'M KEN JACOBSON OF THE NATIONAL
DIABETES AND
DIGESTIVE AND KIDNEY DISEASES
AND I WOULD LIKE TO WELCOME YOU
TO THE 2023 JOHN DALY LECTURE.
THE WE'VE HELD THIS ANNUAL
LECTURE SINCE 209, A YEAR AFTER
JOHN DALY DIED.
THE NIDDK INTRAMURAL RESEARCH
PROGRAM AND THE LABORATORY OF
BIOORGANIC CHEMISTRY TO WHICH I
BELONG AND NOW HEADED BY CAROL
[INDISCERNIBLE] ARE PLEASED TO
NOW RESUME THIS TRADITION POST
COVID.
THIS EVEN SERVES TO HONOR JOHN'S
MEMORY BY RECOGNIZING LEADING
RECEPTOR AND NATURAL PRODUCT
RESEARCHERS SUCH AS BRIAN ROTH
WHO TYPIFIED JOHN DALY'S
SCIENTIFIC IDEALS.
AND WE'VE ALSO RANGED FOR
TROPICAL WEATHER TO GIVE YOU THE
IDEA OF JOHN DALY IN THE RAIN
FOREST.
JOHN W. DALY WAS A PIONEER IN
NATURAL PRODUCTS AND
PHARMAICOLOGGIC RESEARCH FOR
NEARLY 50 YEARS, CAN YOU SO
PHOTOS OF HIS ILLUSTRIUS CAREER
AT NIH.
HE WAS AN INSPIRING MENTOR AND
FRIEND TO MANY NIDDK CHEMISTS.
HE CAME TO NIH AS A POST DOC
WORKING WITH [INDISCERNIBLE] AND
HE LEARNED PHARMACOLOGY FROM THE
NIMH NOBEL LAUREATE JULIUS
AXELROD, HE WAS WELL KNOWN FOR
HIS WORK ON FROG ALKALOIDS,
TOXINS, METABOLISM, SECOND
MESSENGER PATHWAYS, ION CHANNELS
AND NEUROTRANSMITTER RECEPTORS.
HE INTRODUCED MANY OF THE
CENTRAL TOOLS FOR
PHARMAICOLOGICAL RESEARCH, SUCH
AS [INDISCERNIBLE] THE ACTIVATOR
OF ADEN LATE CYCLE ACE,
NICOTINIC AGONIST AND
[INDISCERNIBLE] 1 OF THE MOST
TOXIC SUBSTANCES KNOWN TO HUMAN
KIND.
JOHN WAS PASSIONATE ABOUT
RESEARCH ON GPROTEIN COUPLES
RECEPTORS, THAT IS GPC Rs AND
THE CONCEPT OF STRUCTURE
ACTIVITY RELATIONSHIP IN
MEDICINAL CHEMISTRY.
HE WAS 1 OF THE FIRST TO
RECOGNIZE THAT EACH PART OF A
MOLECULE SERVES ITS OWN ROLE IN
BIOLOGICAL INTERACTIONS.
WHICH ARE NOW BEING REVEALED IN
EXQUISITE AND DYNAMIC DETAIL BY
STRUCTURAL STUDIES.
HE EXPLORED INTRACELLULAR
SIGNALING PATHWAYS INDUCED BY
NATURAL SUBSTANCES, FROM FLORA
AND FAUNA WHICH HE AVIDLY
COLLECTED IN THE JUNGLES OF
SOUTH AND CENTRAL AMERICA, MAD
GAS CAR AND AUSTRALIA, EVEN IN
HIS FINAL YEARS.
THIS YEAR'S RECIPIENT DR. BRIAN
ROTH, MD Ph.D. IS AT THE
FOREFRONT OF BOTH FORMA LOGICAL
AND STRUCTURAL RESEARCH ON GPC
Rs.
HE IS THE MICHAEL HOOKER
DISTINGUISHED PROFESSOR OF
PHARMACOLOGY AT THE UNIVERSITY
OF NORTH CAROLINA SCHOOL OF
MEDICINE AT CHAPEL HILL.
HE COMPLETED HIS DOCTORAL
STUDIES AT ST. LEWIS UNIVERSITY
SCHOOL OF MEDICINE IN 1983, AND
SUBSEQUENTLY TRAINED IN
PHARMAICOLOGY AT NIMH AND THEN,
IN MOLECULAR BIOLOGY AND
PSYCHIATRY AT STANFORD.
HE ACHIEVED THE RANK OF FULL
PROFESSOR OF PSYCHIATRY AND
BIOCHEMISTRY AT CASE WESTERN
RESERVE UNIVERSITY SCHOOL OF
MEDICINE IN CLEVELAND BEFORE
JOINING UNC.
HIS CLINICAL SPECIALTY WAS
TREATMENT RESISTANT
SCHIZOPHRENIA, WHICH HAS LED TO
A BROAD RESEARCH FOCUS ON GPC
Rs AS THE TARGET OF
PSYCHOACTIVE SUBSTANCES.
DR. ROTH AS PUBLISHED ROUGHLY
500 PAPERS IN DIVERSE AREAS OF
MOLECULAR PHARMACOLOGY,
STRUCTURAL BIOLOGY AND SYNTHETIC
BIOLOGY WHICH ARE TYPICALLY
CITED 8000 TIMES A YEAR AND HIS
H-INDEX IS 141.
PERHAPS HE IS BEST KNOWN FOR THE
CHEMO GENETIC PLATFORM
ABBREVIATED DREAD DESIGNER
RECEPTOR EXCLUSIVELY ACTIVATED
BY DESIGNER DRUGS THAT IS WIDELY
USED IN NEUROSCIENCE AND
PSYCHOLOGY LABS AND FOR TD
RECENT ELUCIDATION OF RECEPTOR
STRUCTURES TARGETED BY DRUGS OF
ABUSE AND ANTIPSYCHOTIC DRUGS.
BRIAN ALSO OPERATES THE PDSP, IF
YOU DON'T KNOW WHAT IT STANDS
FOR IT'S THE PSYCHOACTIVE DRUG
SCREENING PROGRAM AT UNC
SPONSORED BY NIMH AS A KIND OF
SERVICE TO THE FIELD WHICH
ALLOWS MANY RESEARCHERS TO
EXPLORE THE POLYPHARMAICOLOGY OF
THEIR FAVORITE CNS ACTIVE
MOLECULES.
HIS LECTURE THEMEATICALLY MERGES
2 OF JOHN'S INTERESTS AND IS
TITLED NATURAL PRODUCTS REVEALED
RECEPTORS FOR PERCEPTION.
AFTER THE LECTURE A QUESTION AND
ANSWER PERIOD, WE WILL HOLD A
RECEPTION WITH BRIAN OUTSIDE
THIS HALL.
IT IS NOW MY DISTINCT HONOR IS
PLEASURE TO INVITE DR. BRIAN
ROTH TO RECEIVE THE AWARD PLAQUE
AND TO DELIVER THE 2023 JOHN
DALY LECTURE.
[ APPLAUSE ]
>>THANKS SO MUCH
FOR THE WONDERFUL INTRODUCTION
AND THE OPPORTUNITY TO VISIT NIH
AGAIN, IT'S BEEN A WHILE SINCE
I'VE BEEN HERE BEFORE COVID.
AND IT'S WONDERFUL TO SEE PEOPLE
IN THE FLESH AS WE SAY.
SO THIS IS A FIGURE THAT WAS
MADE BY A POST DOC OF MINE RYAN
GUMPER.
I FOUND OUT LAST WEEK AT OUR
YEARLY--THE ADMINISTRATIVE PART
OF OUR DEPARTMENTAL MEETINGS
THAT I'M SUPPOSED TO HAVE A
DISCLOSURE SLIDE WHENEVER I GIVE
A TALK SO HERE IT IS.
JUST A FEW THINGS ABOUT JOHN
DALY, I NEVER MET JOHN DALY IN
PERSON, I DON'T EVEN--I WAS
TRYING TO THINK IF I EVER SAW
HIM GIVE A TALK, I NEVER DID,
SADLY.
BUT OF COURSE FORSKOLIN IS USED
IN MY LAB DAILY ACTIVATING
ADENYLATE SIGNIFY CLAYS, AND OF
COURSE CAFFEINE IS USED BY ME
ALL THE TIME TO XEEP ME AWAKE
AND THROUGH THE CENTER, WE USE
EPIBATIDINE, FOR BINDING DATA.
I HAVE NEVER USED THE
BATRACHOTOXINS BUT WE HAVE
GOTTEN INTERESTED IN FROGS SO I
DON'T HAVE ANYTHING TODAY BUT
MAYBE IN THE FUTURE.
SO THE OUTLINE OF MY TALK I WILL
FIRST DISCUSS MY FORAYS INTO
NATURAL PRODUCTS AND THEN, TALK
ABOUT A SUBSET OF THESE THAT ARE
A PSYCHOACTIVE SUBSTANCE AND
TALK ABOUT THE RECEPTORS.
AND THEN GIVE YOU SOME NEW
INSIGHTS INTO A PARTICULAR
NATURAL PRODUCT THAT WE'VE BEEN
INTERESTED IN SOMETIME SILLY
SIGNIN WHICH IS THE PSYCHEDELIC
COMPOUND FROM PSYCHEDELIC
MUSHROOMS.
SO WHEN I THINK ABOUT CHEMICAL
BIOLOGY, I ALWAYS THINK ABOUT
THIS JOURNAL--THIS AND I WILL
RETURN TO THIS THEME TOWARD THE
END OF IT, BUT THIS HIGHLIGHTS
SORT OF A PAPER WE PUBLISHED
SOME YEARS AGO WITH BRYAN
[INDISCERNIBLE]'S LAB.
WE WERE TRYING TO DETERMINE
WHETHER IT'S USEFUL OR NOT TO
ACTUALLY SOLVE A STRUCTURE OF A
RECEPTOR FOR STRUCTURE GUIDED
DRUG DISCOVERY.
AND SO WHAT WE DID IN THIS
PARTICULAR PAPER WAS WE DID A
DOCKING CAMPAIGN AGAINST A
RECEPTOR STRUCTURE WAS THE D3
DOPAMINE RECEPTOR AS WELL AS A
MODEL OF THE RECEPTOR.
AND THAT WAS MADE BY HOMOLOGY,
AND THE STRUCTURES WERE
DIFFERENT BUT BOTH OF THEM WERE
EQUALLY EFFECTIVE FOR
IDENTIFYING COMPOUNDS WITH HIGH
AFFINITY FOR THE D3 RECEPTOR
WITH THE CAVEAT THAT THE
UNIVERSES OF COMPOUNDS THAT WERE
IDENTIFIED FROM EITHER THE MODEL
BASED DOCKING OR THE STRUCTURED
BASE DOCKING WERE COMPLETELY
DISTINCT.
AND THAT'S SOMETHING I WILL
RETURN TO LATER IN THE ERA OF
ALPHA FOLD.
AND I'M GOING TO TALK ABOUT 1
TARGET CLASS IN PARTICULAR,
THESE ARE GPROTEIN COUPLED
RECEPTORS, THIS IS A FILE O GRAM
OF ALL THE GENES, ALL THE OPEN
READING FRAMES IN YOUR GENOME,
THIS IS FROM CRAIG VENTER'S
ORIGINAL PAPER, THIS IS CRAIG
VENTER'S GENOME.
AND WHEN THIS FIRST CAME OUT
THERE WERE 2 THINGS THAT WERE
REALLY INTERESTING TO ME, THE
FIRST IS THAT IF YOU LOOK AT
THIS, THIS SLICE HERE DEVOTED TO
SIGNAL TRANSDUCTION, THAT'S LIKE
AN EIGHTH OF THE GENOME, YOU
VOTED A SIGNAL TRANSDUCTION, IS
GPC Rs CORRESPOND TO ROUGHLY 4
OR 5% OF THE GENOMES, SO THAT'S
A HUGE CHUNK OF YOUR DNA, THAT'S
DEVOTED TO SIGNALING EITHER
UPSTREAM OR DOWN STREAM OF GPC
RS SO THESE ARE--THESE ARE
EXTREMELY IMPORTANT TARGETS AND
TARGETS FOR PHYSIOLOGY.
AND AS I'M SURE YOU ALL KNOW,
G-PROTEIN COUPLED RECEPTORS GET
THEIR NAME BECAUSE THEY COUPLE
TO HETEROPRIMARY G-PROTEINS.
THIS IS A LITTLE CARTOON OF
THEIR ACTION FOLLOWING AGONIST
BINDING.
THERE'S DISASSOCIATION OF THE
HETEROTRI MERRIC G-PROTEIN, AN
EXCHANGE OF GDP FOR GTP AND THEN
THE ALPHA AND BETA SUBGAMMAUE
UNITS ACTIVATE VARIOUS DOWN
STREAM EFFECTORS.
IN THIS CASE HAD IS A PLC
MEDIATED SIGNALING SO ULTIMATELY
YOU WILL GET CALCIUM THAT'S
RELEASED AND THIS--THIS ENTIRE
PATHWAY IS GENERALLY CONSIDERED
TO BE CANONICLE G-RECEPTOR
SIGNALING, RECEPTORS ARE
PHOSPHORYLATED BY THE G-PROTEIN
KINASES.
ARRESTINS BIND AND SERVE TO STOP
SIGNALING THROUGH G-PROTEINS AND
THEN THEY SERVE AS SCAFFOLDS FOR
THEIR OWN FOR DISTINCT SIGNALING
EVENTS ALTHOUGH I MUST SAY IT
STILL REMAINS CONTROVERSIAL AS
EXACTLY WHAT SIGNALING EVENTS
ARE POTENTIALLY MEDIATED BY
ARRESTINS AND WHAT ARE MEDIATED
BY G-PROTEINS BUT YOU GET THE
SENSE HERE THAT FOLLOWING A
SINGLE BINDING EVENT THERE'S
TREMENDOUS DOWN STREAM
APPLICATIONSPLIFICATION AND ALSO
DIVERSIFICATION OF SIGNALING AND
OF COURSE, IT IMMEDIATELY COMES
TO MIND THAT IF WE COULD MAKE
DRUGS THAT BUY A SIGNALING AND
EERLGT OF THOSE PATH--EITHER OF
THOSE PATHWAYS, THEY MIGHT BE
DIFFERENT FROM MEDICATIONS THAT
ARE CURRENTLY AVAILABLE, EITHER
BETTER OR WORSE.
OKAY?
NOW OVER THE YEARS, PRIMARILY
THROUGH THE SCREENING CENTER
THAT I RUN, AND I WAS JUST HAPPY
TO HEAR IT WAS RENEWED FOR
ANOTHER 5 YEARS.
SO CONGRATULATIONS, FOLKS.
WE SET UP A--BASICALLY A UNIQUE,
CONTINUES TO BE UNIQUE SCREENING
RESOURCE WHERE INSTEAD OF
SCREENING AGAINST A SINGLE
MOLECULAR TARGET LIKE IT'S DONE
HERE AT NCATS AND PROBABLY AT
MANY LABS HERE, WE SCREEN LARGE
NUMBERS OF MOLECULAR TARGETS IN
A PARALLEL FASHION AND AS I WILL
SHOW YOU WE HAVE CAPABILITY TO
SCREEN ESSENTIALLY ALL THE GPCR,
ALL THE DRUGGABLE GPC Rs IN A
GENOME IN A SINGLE G-WELL 34
PLATE.
SO WE'RE THEN ABLE TO SCREEN
SINGLE MOLECULES OR CHEMICAL
LIBRARIES AGAINST A VAST
DIVERSITY OF TARGETS.
AND I BASICALLY HAVE USED THIS
RESOURCE, RUN AS A CONTRACT BY
MY LAB AS KEN SAID MAINLY AS A
SERVICE TO THE SCIENTIFIC
COMMUNITY.
SO ANYONE HERE THAT HAS AN
INTERESTING SMALL MOLECULE WE
URGE YOU JUST TO SUBMIT IT FOR
SCREENING.
THERE ARE 3 THINGS I LIKE TO
TELL PEOPLE ABOUT SCREENING,
FIRST IT'S FREE SO IT WON'T COST
YOU ANYTHING OTHER THAN WHATEVER
IT COSTS TO YOU PUT THE COMPOUND
IN A VIAL, SECOND, IT'S
CONFIDENTIAL, SO WE DON'T SHARE
THE INFORMATION WITH ANYONE,
OTHER THAN YOU AND YOU DON'T
HAVE TO TELL US WHAT THE
STRUCTURE OF THE COMPOUND IS.
WE DO NEED TO KNOW THE MOLECULAR
WEIGHT THOUGH AND THE SOLUBILITY
BUT WE DON'T NEED TO KNOW ANY
OTHER INFORMATION ABOUT THE
COMPOUND AND THE THIRD THING
ABOUT THE PROGRAM IS IT'S IP
NEUTRAL SO WE KNOW KNOWN OF THE
INTELLECT RULINNATED ANTIGENS
PROPERTY THAT'S GENERATED ON
COMPOUNDS YOU MIGHT SEND, OKAY?
SO FROM A PATENT PERSPECTIVE
WE'RE CONSIDERED A PAIR OF
HANDS.
SO IT'S FREE, IT'S CONFIDENTIAL
AND IT'S IP NEUTRAL SO
IT'S--THERE'S NOTHING NEGATIVE
THAT COULD COME FROM USING THE
PROGRAM AND TO GIVE YOU A SENSE
OF HOW LARGE THIS PROGRAM IS, I
HAD TO PUT THIS INFORMATION
TOGETHER RECENTLY FOR THE MOST
RECENT REVIEW IN THE LAST 5
YEARS WE WORK WIDE MORE THAN 500
LABS AROUND THE WORLD.
WE CONTRIBUTED TO MORE THAN 500
PAPERS.
SO IT'S A HUGE, HUGE PROGRAM.
AND THESE ARE JUST THE HIGH
IMPACT PAPERS THAT HAVE COME
FROM MY LAB ALONE USING THIS
RESOURCE.
SO WHEY TELL PEOPLE IS IF
THERE'S RESOURCE HAS BEEN USEFUL
FOR ME, IT PROBABLY WOULD BE
USEFUL FOR YOU AS WELL.
AND WE WERE ABLE TO MAKE
SIGNIFICANT ENHANCEMENTS OF THE
SCREENING THROUGH THE DRUGGABLE
GENOME INITIATIVE.
NOW THESE DAYS, THE SCREENING IS
BASICALLY ROBOTIC, AND THE
ANALYSIS IS AUTOMATED.
AND THERE IS MUSIC THAT PLAYS
BUT IT'S USUALLY NOT DAVE
BRUBECK QUARTET BUT THIS GIVES
YOU A SENSE OF BASICALLY THE
SCALE HERE SO WE DO THOUSANDS OF
THESE ASSAYS EVERY DAY, WORKING
WITH ROBOTS.
SO THAT'S OUR SCREENING PROJECT
AND WHAT I WANT TO DO NEXT IS
TAKE YOU THROUGH, FIRST 1
DISCOVERY, WHICH RELATES TO
NATURALLY CONSIDERING
PSYCHOACTIVE SUBSTANCES AND
THERE'S A LITTLE BIT OF A STORY
BEHIND THIS, I THINK SOME OF YOU
PROBABLY NOT MOST OF YOU BUT
SOME OF YOU HAVE SEEN THIS VIDEO
BEFORE, SO, BACK IN THE LATE
1990S, PROBABLY 1998 OR 1999
WHEN I GOT THE VERY FIRST
CONTRACT FOR THE SCREENING
CENTER, I WAS AT CASE WESTERN
RESERVE AND AN UNDERGRAD CAME TO
ME WHO HAD--WHO HAD AN
EXPERIENCE VERY SIMILAR TO WHAT
YOU'RE GOING TO SEE HERE, SO LET
ME START THIS HERE.
SO THIS IS SOMETHING I
DOWNLOADED FROM YouTUBE SO
THAT'S A BONG IN CASE PEOPLE
DON'T KNOW WHAT THAT IS.
SO HERE THIS INDIVIDUAL HAS
BASICALLY TAKEN 1 INHALATION
FROM THIS STUFF HE WAS TOLD IS
BETTER THAN MARIJUANA AND IT'S
GOING TO HAVE A VERY DRAMATIC
EFFECT ON HIM.
SO INITIALLY LAUGHTER.
[LAUGHTER]
AND NOW HE'S HAVING
HALLUCINATIONS.
SO THIS GOES ON FOR ABOUT 20
MINUTES AND THEN HE'S FINE.
AND SO, THE STUDENT HAD COME TO
ME.
HE WAS WRITING A PAPER ON THIS
AND HE WANTED TO KNOW WHAT IT
WAS, GET MORE INFORMATION ON IT.
SO I ASKED HIM WHAT IT WAS AND
WHERE HE GOT IT AND THIS IS IT.
IT'S THIS PLANT S
ALVIA DE MENORA, SIMILAR TO THE
SALVIA DIA THAT GROWS IN YOUR
GARDEN ALTHOUGH IT'S NOT
PSYCHOACTIVE AND THAT GENTLEMEN
THERE IS DANIEL SEBERT WHO
FOUNDED SAGE WISDOM BOTANICALS
AND IN THE EARLY 2000S YOU COULD
PURCHASE THIS OVER THE INTERNET
BASICALLY AND THE ACTIVE GREET
IS SOMETHING CALLED SALVIA
DIVINORUM A, I WILL SHOW YOU THE
STRUCTURE SHORTLY.
SO I LOOKED AT THE STRUCTURE OF
THE COMPOUND AND IT LOOKS LIKE
NO OTHER KNOWN HALLUCIN O GENIC
OR COMPOUND, IT LOOKS LIKE
CHOLESTEROL IF ANYTHING, IT'S
TECHNICALLY A DITERPIN AND I DID
READING ON IT AND I WAS ABLE TO
FIND THE VERY FIRST ACCOUNT BY
DANIEL SEBERT OF SOMEONE SPOKING
PURIFIED SALVINORIN A, SO HE
SAID BASICALLY HE HAD A RAPIDLY
INDUCED PSYCHEDELIC EXPERIENCE
IN WHICH HE WAS TRANSPORTED TO
AN ALTERNATIVE SPACE AND TIME.
SO IT INDUCES SPATIAL TEMPORAL
DISLOCATION.
AND MOST PEOPLE FIND THIS
EXTREMELY FRIGHTENING BUT HE
SAID UREKA I HAVE STUMBLED UPON
THE PSYCHEDELIC ESSENCE OF
SALVIARCS DIVINORUN, SO I SEBT
AN E-MAIL AND ASK HIM IF HE
WOULD SEND US 10-MILLIGRAMS OR
SO OF SALVIA DIVINORUM.
HE JUST WANTED TO KNOW FOR 2
THINGS, RESEARCH PURPOSES OR
PERSONAL USE AND I SAID RESEARCH
PURPOSES AND HE SAID IN THAT
CASE, IT'S FREE.
SO WE RECEIVED A--WE SENT TO
KENTER RICE HERE TO VERIFY THAT
WAS INDEED WHAT WE THOUGHT IT
WAS AND IT WAS SO THIS IS THE
STRUCTURE HERE OF THE COMPOUND,
VERY INTERESTING STRUCTURE.
IT PROVED TO BE SOMEWHAT OF A
CHALLENGE FOR MEDICINAL CHEMISTS
TO MAKE FROM FIRST PRINCIPLES
BUT THEY'RE ARE NOW 3 OR 4 TOTAL
SYNTHESIS OF SALVIA DIVINORUM
AND WE SCREENED IT AGAINST THIS
COLLECTION OF MOLECULAR TARGETS
WE HAVE AND YOU CAN SEE IT WAS
HIGHLY SELECTIVE FOR A SINGLE
TARGET CAN THAT WAS THE CAPPA
OPIATE RECEPTOR AND BY
COMPARISON, AND I WILL RETURN TO
THIS LATER IN THE TALK, WE
SCREENED LSD AND WE KNEW EVEN
LSD HITS MANY, MANY TARGETS.
SO THIS WAS A BIT UNUSUAL THAT
HERE WE HAVE THIS LIPID
BASICALLY THAT'S ACTIVATING
RECEPTOR FOR PEPTIDES AND IT
DOES IT IN A VERY, VERY
SELECTIVE WAY.
SO DANIEL SEBERT WAS VERY
INTERESTED IN THIS INFORMATION.
SO I SENT IT TO HIM.
AND HIS LIFE HAS BASICALLY BEEN
DEVOTED TO STUDYING THIS PLANT.
HE WAS A LITTLE BIT DISAPPOINTED
THAT IT WAS THE CAPPA OPIATE
RECEPTOR AND HE SAID HE DID NOT
BELIEVE THAT IT WAS THE CAPPA
OPIATE RECEPTOR, HE FELT THERE
HAD TO BE--BECAUSE IT INDUCED
SUCH A MARVELOUS EXPERIENCE IT
COULD NOT POSSIBLY DUE TO CAPPA
OPERATING GLOBALLY PILOT
PROJECTATE RECEPTOR BECAUSE WHAT
THE DOGMA S&P THAT CAPPA
AGONISTS ARE DISFOREVERRIC.
THAT'S TRUE IN ANYTHING OTHER
THAN YOU HAD HANS, IT TURNS OUT.
HUMANS ARE NOT DYSPH ORIC, SO HE
PROPOSED THIS EXPERIMENT WHERE
HE WOULD PRETREAT HIMSELF WITH
NARCAN AND THEN HE WOULD SMOKE
SALVIA DIVINORUM AND THEN IT
BLOCKS THE CAPPA U AND OPIATE
RECEPTORS AND I SENT HIM BACK AN
E-MAIL SAYING I THINK THIS IS
VERY BAD IDEA.
YOU COULD DIE.
AND 1 OF THE CONCERNS I HAD WAS
THAT HE WOULD BE DEAD.
AND THERE WOULD BE AN E-MAIL IN
HIS HANDS SAYING, YES THIS IS A
GREAT EXPERIMENT GO AHEAD AND DO
IT.
[LAUGHTER]
SO I WOULD END UP IN THE
NEW YORK TIMES FOR THE WRONG
REASON BUT I TOLD HIM THAT WAS A
VERY BAD IDEA AND I DON'T
RECOMMEND IT BUT I WANT YOU TO
TAKE A LOOK AT THE DATE, IT SAYS
27 MARCH, 2002.
YOU CAN SEE A TIME STAMP 1:53 IN
THE AFTERNOON, OKAY.
SO I WENT HOME.
NEXT DAY, I HAD THIS 28
MARCH 0800, OH THE OTHER THING I
TOLD HIM WAS IF YOU DO THIS
EXPERIMENT, SO BY THEN WE HAD
WRITTEN UP A PAPER AND I SAID
WE'RE NOT GOING TO ENCLUED THE
HUMAN DATA IN THE PAPER, OKAY?
BECAUSE WE NEED HUMAN USE AND
ALL THAT STUFF, BUT HE DID THE
EXPERIMENT AND LOW AND BEHOLD
THE EFFECTS WERE BLOCKED, MORE
OR LESS COMPLETELY BY
SALVIA DIVINORUM A AND BY
NALOXONE, AND SUBSEQUENTLY AS I
WILL SHOW YOU, IT'S CLEAR THAT'S
HOW IT WORKS.
BUT I PULLED EVERYBODY IN MY LAB
TO LOOK AT THIS BECAUSE I SAID
LOOK, THIS IS SOMETHING THAT
WILL NEVER HAPPEN TO YOU IN YOUR
LIFE WHERE YOU MAKE A DISCOVERY
IN THE LAB AND THE NEXT DAY IT'S
VALIDATED IN HUMANS OKAY, SO, SO
THERE YOU GO.
SO OF COURSE, WE DID THE SORT OF
CLASSICAL STUDIES, LOOKED AT
CAPPA KNOCKOUT MICE, HAS NO
EFFECT.
OPIATE EFFECT BLOCKS IT IN
NONHUMAN PRIMATES.
AND SUBSEQUENTLY THERE HAVE BEEN
MULTIPLE STUDIES SHOWING THAT
THE APPROPRIATE OPIATE
ANTAGONIST WILL BLOCK IT IN
HUMANS SO IT WORKS THROUGH CAPPA
RECEPTORS.
NO QUESTION.
SO THE QUESTION THAT WAS
LINGERING THOUGH IS ARE THERE
ANY OTHER MOLECULAR TARGETS THAT
THIS COMPOUND INTERACTS WITH
BECAUSE AT THE TIME WE HAD
THIS--IT WAS FOR THE SCIENTIFIC
COMMUNITY IT WAS A BIG
COLLECTION OF MOLECULAR TARGETS
BUT STILL RELATIVELY SMALL.
AND SO, A NUMBER OF YEARS LATER,
WE BUILT THIS RESOURCE WHICH IS
AVAILABLE THROUGH AGENE WHICH WE
CALL PREOF THE O-TANGO WHICH
ALLOWS A SINGLE 384 WELL PLATE
THE ABILITY TO SCREEN ALL THE
RECEPTORS ON THIS, THIS IS A
FILE O GRAM OF THE HUMAN GPC R,
SO EVERY PLACE THERE'S A CIRCLE
FILLED OR COLORED THAT'S WHERE
WE HAVE A VALIDATED ASSAY AND
YOU CAN ORDER THE ENTIRE THING
FOR ABOUT A THOUSAND DOLLARS IN
AJENE.
AND SO THIS ALLOWS FOR UNBIAS
SCREENING OF NEARLY THE ENTIRE
DRUGGABLE GPCR AND WE'RE NOT
ABLE TO GET FRIZZLED OR TASTING
RECEPTORS YET THROUGH THIS ASSAY
SYSTEM.
SO WE THROUGH THE ALIEWMINATING
DRUG INITIATIVE, WE TESTED THE
SALVIA DIVINORUM A AGAINST THIS
AND OTHER TARGETS AND NO
SURPRISE IT'S A CAPPA AGONIST.
HAS ABOUT A THOUSAND FOLD LESS
AFFINITY FROM NEW RECEPTORS AND
HITS NO OTHER TARGET SO THIS
IS--AS THESE THINGS GO, THIS IS
VERY, VERY UNUSUAL TO GET A
COMPOUND WHICH IS EXTREMELY
POTENT FOR A SINGLE MOLECULAR
TARGET AND IS A NATURAL PRODUCT.
SO THIS IS--THIS IS VERY
UNUSUAL, WE ULTIMATELY WERE
INTERESTED IN UNDERSTANDING HOW
IT IS THAT SALVIA DIVINORUM A
AND OTHER DRUGS BIND TO CAPPA
RECEPTORS, AND ULTIMATELY WE'RE
ABLE TO GET A--SOMEBODY WAS
ASKING ABOUT NANO BODIES, 1 OF
THE STUDENTS SO THIS A NANO BODY
ACTIVE STATE OF THE CAPPA
RECEPTOR THAT WE SAW BY X-RAY
CRYSTALLOGRAPHY BACK IN THE DAYS
WHEN PEOPLE WERE STILL DOING
X-RAY CRYSTALLOGRAPHY AND THIS
ALLOWED US TO GET USE OF
INSIGHTS INTO DRUG BINDING AND
SALVIA DIVINORUM A BINDINGA THE
RECEPTOR.
SUBSEQUENTLY MY MOST DOC HERE
TAU, NOW HAS A FAC UMENTY
POSITION AT WASHINGTON
UNIVERSITY IN ST. LOUIS AND JUST
A FEW MONTHS AGO HE PUBLISHED A
BEAUTIFUL PAPER IN NATURE
SHOWING SALVIA DIVINORUM A
ANALOGUE BOUND TO THE
B-RECEPTOR.
SO IT TURNS OUT, NONE OF OUR
MODELS WERE CORRECT AND THE
STRUCTURE WE THINK IS CORRECT.
AND ALONG THE WAY, MY LAB
INITIALLY WITH RAY STEVENS WHO
WAS THE FIRST, I GUESS THE FIRST
LECTURER HERE, STARTING IN I
THINK 2007 OR SO WE STARTED
COLLABORATING WITH HIM ON
SOLVING AND CHARACTERIZING GPCR
STRUCTURES, SOLVE A NUMBER OF
THOSE WITH HIM AND BADEEM, AND
MORE RECENTLY COLLABORATED WITH
ERIC [INDISCERNIBLE]'S LAB AND
THEN OF COURSE MY OWN LAB HAS
SOLVED MANY, MANY, MANY
STRUCTURES AND I WILL JUST TELL
YOU ABOUT A COUPLE OF THEM TODAY
BUT THOSE ARE--THOSE ARE LISTED
THERE.
SO THIS IS--THIS HAS BEEN A VERY
FRUITFUL AREA OF RESEARCH IF FOR
NOTHING ELSE, MY POST DOCKS HAVE
BEEN ABLE TO GET JOBS AFTER THEY
PUBLISHED THEIR PAPERS AND THERE
ARE JUST 2 RECENT PAPERS I WANT
TO HIGHLIGHT.
THE TOP 1 I THINK, I CONSIDER
THIS 1 OF THE 2 BEST PAPERS I
EVER PUBLISHED IN MY LIFE.
THIS PROBABLY MEANS NO 1 READS
IT BUT FOR THOSE OF YOU WHO WORK
WITH CHEMO GENETICS, I KNOW
PEOPLE--IF YOU'RE IN THE
NEUROSCIENCES, EVERYBODY USES
THEM.
IT REALLY SHOWS VERY NICELY HOW
WE ARRIVED AT THOSE BY DIRECTED
EVOLUTION AND THE SECOND IS
AGAIN THIS WILL BE A LEGACY
PAPER, THIS WILL BE THE
STRUCTURE OF THE ENTIRE HUMAN
OPIATE RECEPTOR HUMAN FAMILY WE
DID WITH ERIC XU.
ALL RIGHT.
SO THE OTHER THING WE WANTED TO
REALLY UNDERSTAND ABOUT
SALVIA DIVINORUM A IS WE
BASICALLY VERIFIED IT'S HIGHLY
SELECTIVE AT THE CAPPA RECEPTOR
ARE THERE ANY DOWN STREAM OF THE
CAPPA RECEPTOR IS THERE ANYTHING
THAT'S UNUSUAL ABOUT
SALVIA DIVINORUM A VERSUS OTHER
CAPPA AGONISTS?
AND WHEN WE REALLY GOT
INTERESTED IN THIS THERE WERE NO
REALLY READILY AVAILABLE
RESOURCES TO LOOK AT ALL THE
VARIOUS G-PROTEINS AND ARRESTINS
THAT ARE DOWN STREAM OF A SINGLE
RECEPTOR SO WE BUILT A RESOURCE,
WE CALL IT TRUE PATH.
IT ALLOWS FOR THE UNBIASED
SCREENING, AND PROFILING OF DRUG
ACTIONS DOWN STREAM OF EVERY
ALPHA SUBUNIT, EVERY BETA AND
ALPHA SUBUNIT, EVERY CONCEIVABLE
COMBINATION AS WELL AS ALL THE
ARRESTINS.
AND TO MAKE A LONG STORY SHORT
WE FOUND THAT SALVIA DIVINORUM A
IS NOT PARTICULARLY UNUSUAL
PREPARED TO OTHER CAPPA AGONISTS
IN TERMS OF DOWN STREAM
DIGINALLING BUT THERE ARE OTHER
RECEPTORS AS WELL.
AND AGAIN THIS IS AVAILABLE
THROUGH AJENE.
SO I WANT TO BRIEFLY HIGH LIE
OTHER--SO, IN TERMS WAS THEME OF
MY TALK WHICH IS NATURAL
PRODUCTS AND THE RECEPTORS OF
PERCEPTION, SO, YOU CAN SEE THAT
THIS SINGLE MOLECULE
SALVIA DIVINORUM A HIGHLY
SELECTIVE FOR THE CAPPA RECEPTOR
HAS A HUGE EFFECT ON HOW PEOPLE
VIEW REALITY, HOW THEY PERCEIVE
REALITY.
OKAY, SO BECAUSE OF THAT, I
WOULD SAY THAT THE CAPPA
RECEPTOR IS A RECEPTOR FOR
PERCEPTION.
IT'S JUST NOT FOR THE TYPE OF
PERCEPTION THAT WE NORMALLY
THINK, IT'S PERCEPTION THAT'S
INTERNALLY GENERATED, OKAY?
WHAT ABOUT OTHER TYPES OF
SENSATION?
WELL ANOTHER TYPE OF PERCEPTION
IS THE SENSE OF ITCH, RIGHT?
SO THIS IS MORPHINE.
FOR THOSE WHO ARE INTERESTED IN
THE HISTORY OF NATURAL PRODUCTS,
THIS IS TYPICALLY DESIGNATED AS
THE FIRST NATURAL PRODUCT THAT
WAS PURIFIED IN THE 1800S AND
GIVEN THE NAME MORPHINE AFTER
THE GOD MORPHUOUS, THE GOD OF
SLEEP OR DREAMS.
AND TYPICALLY WHEN YOU THINK
ABOUT MORPHINE YOU THINK ABOUT
THE CLASSICAL OPIATE RECEPTORS
BUT THERE ARE A NUMBER OF VERY
INTERESTING SIDE EFFECTS OR
ADVERSE EEIVETS THAT OCCUR WITH
MANY OPIOIDS, 1 OF WHICH IS
ITCH.
SO MANY, MANY PEOPLE HAVE
EXTREME ITCHING BOUTS WHEN THEY
TAKE OPIATES.
AND IT TURNS OUT THAT THIS IS
DUE TO A PSEUDOALLERGIC REACTION
DUE TO THE INTERACTION OF
MORPHINE WITH A PARTICULAR
RECEPTOR THAT'S FOUND ON MASS
CELLS THAT CAUSES MASS CELL
DEGRANULATION, THIS IS THE
RECEPTOR MRGPRX2, FOR MASS
G-PROTEIN COUPLED RECEPTOR
EXCLUSIVELY FOUND IN PRIMATES
MRPMRX2.
AND BASED ON THIS SINGLE FINDING
THAT MORPHINE WAS A POTENT PLUS
PLUS AND MINUS MORPHINE ARE
EQUALLY GOOD AGONISTS FOR
MRGPRX2, BUT FENTYNL IS NOT.
THIS RECEPTOR IS ALSO ACTIVATED
BY NEUROPEPTIDES, INCLUDING
OPIATE LIKE COTTERY STATIN AND
BASED ON THIS WE WERE ABLE TO
SOLVE STRUCTURES BY ELECTRON
MICROSCOPY OF THIS PARTICULAR
RECEPTOR, TURNS OUT IT'S COUPLES
TO MULTIPLE G-PROTEINS, THERE IS
SOME DEBATE IN THE FIELD ABOUT
WHICH G-PROTEIN ACTUALLY IS
INVOLVED IN MASS CELL
DEGRANULATION, OTHERS SAY GQ,
OTHER SAY GI, WE SAY BOTH A
SMALL MOLECULE AGONIST, AND
THERE ARE NOW SMALL MOLECULE
ANTAGONIST FOR MRGPR X2 THAT ARE
IN CLINICAL TRIALS FOR TREATING
ITCH AND A VARIETY OF OTHER
INDICATIONS.
SO OPIATES ARE ALSO RESPONSIBLE
FOR THE SENSATION OF PAIN AND OF
COURSE WE HAVE SOLVED MANY, MANY
OPIATE RECEPTOR STRUCTURES.
THERE ALSO IS THIS--IS THIS SORT
OF RELATED RECEPTOR MRGPR X1 SO
THIS IS A RECEPTOR IN THIS
FAMILY ALTHOUGH IT APPEARS TO
BE--TO HAVE BEEN EVOLVED TO GATE
SENSATIONS OF PAIN THROUGH
DORSAL ROOT GANGLIA NEURONS.
IN FACT FOR THOSE WHO STUDY
NEURONEURON SAYS THERE ARE
EXPRESSING NEURONS THAT ARE VERY
SPECIFIC SO IT TURNS OUT THAT
OPIATE PEPTIDES ALSO INARCT WITH
MRGPRX1 BUT IT TURNS OUT IT'S
THE OTHER END OF THE PEPTIDE SO
TO GIVE YOU AN EXAMPLE, THERE'S
THIS OPIATE PEPTIDE CALLED BAM
1-22.
WHERE THE FIRST 8 OR SO AMINO
ACIDS BASICALLY ARE DISCIPLINARY
NOEVERIN.
AND INTERACT WITH OPIATE
RECEPTORS, AND THEN THE AMINO
ACIDS 8-22 ACTUALLY ACTIVATE
THIS PARTICULAR RECEPTOR.
SO YOU HAVE THIS VERY
INTERESTING SITUATION, WHERE 1
CLEAVAGE PRODUCT, BAM 1-8
ACTIVATE OPIATE RECEPTORS TO
REDUCE PAIN AND THEN 8-22
ACTIVATES MRGPRX1 RECEPTORS TO
REDUCE PAIN.
SO WE THINK THIS IS PROBABLY A
REALLY GOOD TARGET AGAIN FOR
PAIN.
BIOACIDS, IT TURNS OUT ALSO
INDUCE ITCH UNLIKE OPIATE
PEPTIDES AND SMALL MOLECULE
OPIOIDS THESE ARE NEGATIVELY
CHARGED SO 1 OF THE THINGS
THAT'S VERY COMMON AMONG DRUG
THAT ACTIVATE MRGPH X2 IS
THEY'RE AUGHT PROFILES, THERE'S
THIS COMPANION RECEPTOR CALLED
MRGPRX4 WHICH IS ACTIVATED BY
NEGATIVELY CHARGED SUBSTANCES.
SO IT TURNS OUT THAT WE HAVE
THIS RECEPTOR SYSTEM THAT HAS
EVOLVED IN THE CASE OF X2 AND
X4, PROBABLY DOES NOT HAVE
ENDOGENOUS LIGANDS BUT HAS
EVOLVED AS A SENSOR FOR NOXIOUS
SUBSTANCES IN THE ENVIRONMENT,
OKAY?
AND IN THIS CASE, 1 RECEPTOR HAS
BEEN--HAS EVOLVED TO SORT OF BE
SENSITIVE TO POSITIVELY CHARGED
PURE ANTIGEN AND THE OTHER TO
NEGATIVELY CHARGE FOR ANTIGENS.
VERY INTERESTING AND WHEN YOU
LOOK AT THE STRUCTURES IT MAKES
COMPLETE SENSE BY THE STRUCTURE.
IN 1 CASE THERE'S A HUGE
POSITIVELY CHARGED WELL, THE
OTHER CASE A NEGATIVELY CHARGED
WELL.
SO VERY, VERY INTERESTING.
AND THAT'S MORPHINE.
ALL RIGHT, SO, ONCE WE HAD ALL
THESE STRUCTURES I USED TO TELL
THIS JOKE THAT AT THE END OF
EVERY STRUCTURE PAPER, THE LAST
SENTENCE OF EVERY ABSTRACT AND
THE LAST SENTENCE OF ANY
DISCUSSION IS THIS STRUCTURE
WILL BE IMPORTANT FOR DRUG
DISCOVERY, RIGHT?
AND THEN THAT'S IT, YOU NEVER
HEAR ANYTHING ELSE ABOUT IT.
[LAUGHTER]
OKAY, SO WE DECIDED TO DO
SOMETHING ABOUT THAT.
SO OVER THE YEARS I COLLABORATED
MAINLY WITH THE [INDISCERNIBLE]
LAB AT UCSF, TO MAKE SMALL
MOLECULE PROBES FOR A NUMBER OF
THESE PRIMARILY UNDERSTUDIED
RECEPTORS FOR WHICH WE HAD
STRUCTURES OR STRUCTURAL
INFORMATION, SO THESE ARE JUST
VARIOUS, YOU KNOW VARIOUS
RECEPTORS HERE.
IF YOU--IF YOU'RE INTERESTED IN
READING ANY OF THESE PAPERS, I
WOULD HIGHLIGHT 2, SO THIS IS A
REALLY INTERESTING PAPER, WHERE
WE USE STRUCTURE TO OPTIMIZE A
COMPOUND THAT WAS IN THE PATENT
LITERATURE WHICH IS A COMMON
PROBLEM BASICALLY, IF THERE'S
SOMETHING GOOD IN THE PATENT
LITERATURE BUT IT'S NOT GOOD
ENOUGH AND YOU NEED TO OPTIMIZE
IT, YOU DON'T KNOW HOW, SO WE
GOT A STRUCTURE.
AND BY COMPARISON, AROUND THE
SAME TIME WE PUBLISHED A PAPER
IN J-MED CHEM WHERE WE DIDN'T
HAVE A STRUCTURE BUT WE DID
DOCKING AGAINST A MODEL AND IT
TURNED OUT THE COMPOUND THAT WE
GOT FROM STRUCTURE GUIDED
DISCOVERY WAS SELECTIVE AND
POTENT AND THE COMPOUND WE GOT
FROM IT WAS STRICTLY MODELING
BASED APPROACH WAS NOT, NOT AS,
SO IT DOES, IT DOES HELP AND I
THINK THAT'S--THAT PAPER IN THIS
PARTICULAR IS A PRETTY GOOD 1.
THE OTHER 1 IS--AND THAT COMES
COMPLETELY FROM MY LAB, THE
OTHER 1 IS THIS NICE 1 ON THE
CB2 RECEPTOR FROM
[INDISCERNIBLE]'S LAB AND MY
LAB, WHERE HE HAS DEVISED A
NOVEL APPROACH FOR ULTRA LARGE
SCALE DOCKING THAT HE CALLS
D-SYNTHESIS FOR VIRTUAL SYNTH
COPD AND IT INVOLVES THE DOCKING
OF FRAGMENTS OF BUILT BY
COMPUTER BY BUILDING PLOKS AND
USING THIS YEAR NOW ABLE TO
INTERROGATE TRILLIONS OF
MOLECULES COMPUTATIONALLY.
SO THESE ARE BOTH REALLY, REALLY
NICE EXAMPLES OF THAT.
SO THE TIME THEY HAVE REMAINING
I WANT TO TALK ABOUT
PSYCHEDELICS.
AND PSYCHEDELICS HAVE SORT OF A
CHECKERED HISTORY BUT YOU KNOW
RECENTLY LIKE LAST 3 YEARS OR
SO, 3 OR 4 YEARS THEY'VE BECOME
QUITE POPULAR IN THE
NONSCIENTIFIC AREA.
AND SOMEWHAT POPULAR AMONG
SCIENTISTS AS WELL.
AND BEFORE I TALK TO THEM, I
WOULD LIKE TO GIVE EVERYBODY MY
DEFINITION OF A PSYCHEDELIC.
SO, THIS IS MY DEFINITION, IT
ALSO TURNS OUT THIS IS THE
DEFINITION THAT THE FDA USES,
IT'S ALSO THE DEFINITION THAT
THE DEA USES AND IT'S ALSO THE
DEFINITION THAT THE EUROPEAN
REGULATORY AGENCIES USE, OKAY?
AND THIS IS THE DEFINITION THAT
MY LAB AND EVERYBODY ELSE IN THE
FIELD HAS USED SINCE THE 1970S,
BASICALLY.
SO PSYCHEDELIC DRUGS ARE 5 HT2A
AGONIST WHICH INDUCE LSD-LICK
ACTIONS IN HUMANS.
SO IF YOU READ, MDMA, SO ECSTAS
EXPE KETAMINE, THESE ARE NOT
PSYCHEDELIC DRUGS, THEY'RE
HALLUC NO GENERATEDS.
THE REASON I GO INTO THIS IS
THAT I FREQUENTLY GET
INTERVIEWED BY NEWS MEDIA BY
PSYCHEDELICS SINCE I'M 1 OF THE
FEW PEOPLE WHO HAS A GRANT TO
STUDY PSYCHEDELICS SO I'M 1 OF
THE FEW SCIENTIFIC EXPERTS OUT
THERE AND WHAT I HAVE FOUND IS
TAKEN--THEY KETAMINE IS
CONSIDERED A PSYCHEDELIC, MDMA
IS A PSYCHEDELIC, IT'S ALMOST
LIKE ANY DRUG THAT ALTERS HOW
YOU FEEL IS CONSIDERED A
PSYCHEDELIC.
OKAY, BUT WHAT I LIKE TO POINT
OUT IS THERE'S A SCIENCE BEHIND
THIS, SO, THESE ARE--THESE DRUGS
ARE CLASSIFIED AS HALLUCIN O
GENIC AGENTS BECAUSE THEY INDUCE
HA LIEWTIONZINATIONS AND WHICH
INCLUDE DRUGS LIE LSD,
PSILOCYBIN AND THERE ARE DRUGS
THAT INDUCE DELERIUM, SO THESE
ARE GABBA RECEPTOR MODULATORS
FROM AMINITTA AS WELL AS
[INDISCERNIBLE] OCCASIONS FROM
MUSHROOMS AND OTHER SOURCES SO
THEY INDUCE A DELERIUM AND THERE
ARE DRUGS THAT INDUCE A DREAM
LIKE STATE THAT ARE CALLED
ONERAGENSS AND THESE ARE 1S LIKE
SALVIA DIVINORUM AND
[INDISCERNIBLE].
NOW THE THING ABOUT THIS
CLASSIFICATION SCHEME IS THAT
EVERYTHING IS CLASSIFIED BY
MECHANISM OF ACTION, SO THESE
ARE CAPPA AGONIST, SCOPOLAMINE
AND AMANITA, IS ARE AGONISTS AND
ALL THOSE DRUGS ARE THE HTMP2 A
AGONISTS.
AND THOSE ARE THE DRUGS I'M
GOING TO TALK ABOUT IN THE TIME
I HAVE REMAINING.
NOW THEY HAVE DIFFERENT EFFECTS
IN HUMANS SO KETAMINE IS
DIFFERENT FROM PSILOCYBIN, IN
HUMANS.
SO THIS IS AN OLD VIDEO I PULLED
FROM YouTUBE OF A WOMAN IN THE
1950 WHO IS WAS GIVEN LSD AND
SHE'S HAVING A PSYCHEDELIC
EXPERIENCE HERE.
IT'S HERE, CAN YOU FEEL IT?
EVERYTHING IS COLORED AND I CAN
FEEL THE AIR.
SO SHE'S HAVING SYNESTHESIA,
RIGHT?
I'M FINE WITH IT, CAN'T YOU SEE
IT?
>>I'M TRYING.
>>I FEEL FREE.
>>OKAY, SO THAT'S A PSYCHEDELIC
EXPERIENCE.
>>OKAY, SOME PEOPLE HAVE MAYBE
EXPERIENCED THAT.
AND HERE IS A RECENT KETAMINE
EXPERIENCE.
[♪ MUSIC ♪]
>>SO FIRST THING TO NOTICE IS
HE DOESN'T KNOW WHERE HE IS.
SO HE'S PRETTY OUT OF IT.
>>[INDISCERNIBLE]
>>INCREDIBLE.
>>WHAT ARE THE THOUGHTS IN YOUR
MIND?
>>THAT WE'RE ALL CONNECTED.
THAT WE'RE ALTOGETHER.
WE--IT'S JUST SO CLEAR--WE ARE
ALL IN THIS TOGETHER.
WHAT IS THIS, WE'RE ALL IN THIS
TOGETHER IN WHAT IS THIS?
>>WELL I MEAN LIKE OUR LIVES,
OUR PURPOSE, OUR SOUL.
WE'RE ALL--IT'S CRAZY HOW WE'RE
ALL FEELING.
>>ALL RIGHT, SO YOU CAN SEE
THAT'S A DIFFERENT--DIFFERENT
EXPERIENCE.
THEY'RE BOTH HAVING AN APPARENT
EXPERIENCE OF 1NESS BUT THE
PHENOMENOLOGY OF THE EXPERIENCE
IS QUITE DIFFERENT THAT'S WHY I
LIKE TO REFER TO PSYCHEDELICS AS
DIFFERENT DRUGS SO THEY HAVE
UNIQUE PROPERTIES WHICH HAVE
RECENTLY BEEN IN LARGE PART THE
REASON FOR THEIR, I WOULD SAY
INTEREST AMONG MEDICAL
PROFESSIONALS AND OTHERS AND
THESE WERE STUDIES THAT WERE
DONE PRIMARILY BY 2 GROUPS,
GRIFFITH'S GROUP AT HOPKINS AND
THE GROUP AT NYU BASICALLY
PUBLISHED BACK-TO-BACK PAPERS IN
2016 SHOWING THAT A SINGLE DOSE
OF PSILOCYBIN, SHOWED A RAPID
EFFECT ON DEPRESSION, SO MUCH SO
THAT A LOT OF PATIENTS WERE NO
LONGER DEPRESSED AFTER A DOSE OF
PSILOCYBIN, THEY WERE STILL NOT
DEPRESSED AFTER A YEAR, SO THESE
WERE PEOPLE THAT WERE TREATMENT
RESISTANT, HAD VERY, VERY
SERIOUS DEPRESSION, HAD BEEN
TRIED WITH MULTIPLE OTHER
MEDICATIONS, NO EFFECT.
BASICALLY GIVEN A SINGLE SORT OF
REALLY A MAZZIVE DOSE OF
PSILOCYBIN AND THEY HAD A
INTENSE PSYCHEDELIC EXPERIENCE,
THE NEXT DAY THEY WERE FINE AND
THEIR DEPRESSION WAS GONE FOR UP
TO A YEAR.
OKAY, SO THIS IS IN LARGE
MEASURE HAS BEEN FUELING THE
RECENT INTEREST IN PSYCHEDELICS
BECAUSE OF THE POTENTIAL FOR
THEIR TRANSFORMATIVE THERAPEUTIC
UTILITY FOR NEARLY EVERY
NEUROPSYCHIATRIC DISORDER WITH
THE EXPRESSION OF DISEASES LIKE
SCETS FRENNIA AND BIPOLAR
DISORDER WHERE THEY WOULD MAKE
YOU WORSE, BASICALLY.
AND MDMA WHICH IS NOT A
PSYCHEDELIC BUT SOMETIMES LUMPED
INTO THAT NOW HAS 2 POSITIVE
PHASE 3 CLINICAL TRIALS FOR
TREATING POST-TRAUMATIC STRESS
DISORDER AND FOR THOSE WHO ARE
INTERESTED, I URGE YOU TO READ
THE ORIGINAL PAPER WHICH WAS TUB
PUBLISHED ONINATE AND YOU ARE
MEDICINE ASK TREAT A LOT OF
PEOPLE WITH PTSD IN MY DAY WHEN
I WAS TREATING PSYCHIATRY THERE
WAS NOTHING THAT HAD THIS EFFECT
OF MDMA.
THE EFFECT IS HUMONGOUS AND IS
ROBUST.
AND LIKELY MDMA WILL BE APPROVED
NEXT YEAR AND IT WILL TRANSFORM
HOW WE TREAT POST-TRAUMATIC
STRESS DISORDER.
AS WELL THE PSYCHEDELIC DRUGS
LIKELY WILL BE APPROVED FOR
DEPRESSION, OBSESSIVE COMPULSIVE
DISORDER ISSUES CLUSTER
HEADACHES A HUGE SWATH OF
THINGS, THIS IS ALSO HOW
PSYCHIATRIC CARE WILL BE GIVEN
IN THE UNITED STATES AND
ELSEWHERE, THE PROBLEM IS WE
HAVE ALMOST NO INFORMATION ABOUT
HOW THEY WORK.
OKAY?
SO SOME YEARS AGO, WHEN THE NIH
FINALLY FUNDED ME TO STUDY
PSYCHEDELICS, I TOLD THE
STUDENTS, I WROTE GRANTS TO
STUDY PSYCHEDELICS FROM THE
1990S AND I THEY NEVER GOT
FUNDED.
MY FIRST GRANT GOT FUNDED IN
2017 SO IT TOOK A LONG TIME BUT
THE FIRST THING WE DID WAS JUST
LOOK AT PHARMAICOLOGY AND WE
FOUND IT HAS A EXTREMELY
COMPLICATED PHARMAICOLOGY AND
YOU CAN SEE INTERACTING WITH
EVERY BIOGENIC AMINE RECEPTOR IN
THE HUMAN GENOME BUT WE THINK
IT'S ONLY THE INTERACTION WITH
THAT 1 RECEPTOR HERE, THE 5 HT2
A THAT'S RESPONSIBLE FOR ITS
ACTION.
AND YOU KNOW AS I SAID WE HAD
BUILT ALL OF THESE RESOURCES TO
SCREEN DRUGS SO WE DECIDED TO
MAKE A FORAY INTO THE
PSYCHEDELIC DRUG SPACE AND SO WE
IDENTIFIED ULTIMATELY 44 IKE
DELATWALLIC DRUGS, DRUGS THAT
ARE KNOWN TO BE PSYCHEDELIC IN
DRUGS IN HUMANS OF VARIOUS
CHEMICAL CLASSES AND THEN WE
SCREENED THEM USING THE VARIOUS
ASSAY PLATFORMS THAT I MENTIONED
SO AGAIN 320 GPC Rs AND THEN
QUAWBTIFIED THE SIGNALING
THROUGH EVERY TRANSDUCER.
AND THIS IS WHAT WE GET, SO THIS
IS A HEAT MAP OF THE DATA SO
THESE ARE DRUGS GOING DOWN HERE
THESE ARE YOU ARE RECEPTORS
GOING UP HERE.
YOU CAN IMAGINE THIS WAS A LOT
OF WORK BY [INDISCERNIBLE] AND
YOU CAN SEE THIS IS AN LSD
ANALOGUE, IT'S ACTIVE IN
EVERYTHING, IT'S BECAUSE IT
INHIBITS LUCIFERASE DEGRADATIO,
SO IT'S A LUCIFERASE STABILIZER
BUT CAN YOUEE THERE ARE 3
GENERAL FAMILIES OF RECEPTORS
THAT ACTIVATE, SEROTONIN,
DOPAMINE AND ADRENAL CANCERERGIC
BUT YOU WOULD BE HARD PRESSED TO
IDIDN'TIFY SINGLE RECEPTOR OR A
SINGLE TRANSDUCTION PATHWAY THAT
IS SHARED BY ALL PSYCHEDELICS.
IT TURNS OUT THAT IT'S--THIS
IS--THIS IS PROBABLY THE MAGIC
REGION HERE BUT AGAIN IF YOU
WERE--IF YOU HAD--IF YOU HAD NO
IDEA HOW THESE DRUGS WORKED
THERE WOULD BE NO WAY YOU WOULD
PICK THIS OUT, BASICALLY,
THERE'S NO INFORMATION FROM
SEQUENCING YOUR GENOME, DOING
SINGLE CELL RNA, LOOKING AT THE
ALAN BRAINAT LAS PINTAS, ET
CETERA, WHATEVER LEADS YOU TO
THE 5 HT2 A RECEPTOR, THE ONLY
WAY YOU WOULD KNOW THAT IS
THROUGH PHARMACOLOGY, AND THE
REASON WE KNOW THIS IS BECAUSE
OF THIS DATA HERE.
SO IT WAS KNOWN BY RICHARD
GLENON BACK IN THE 1980S THAT
THE PSYCHEDELIC ACTIONS OF THOSE
DRUGS CORRELATED VERY WELL WITH
THEIR AFFINITY TO BIND TO THE
ACTIVE STATE OF THE 5 HT2 A
RECEPTOR AND THEN SOME YEARS
LATER GONZALEZ MASO DID STUDIES
IN KNOCKOUT MICE AND WE FOUND
THEY DON'T RESPOND TO
PSYCHEDELICS BUT REALLY THE BEST
EVIDENCE ACTUALLY IS THE HUMAN
DATA.
SO THERE ARE NOW A NUMBER OF
STUDIES, THIS WAS DONE BY FRAN
[INDISCERNIBLE] GROUP IN
SWITZERLAND WHERE THEY DID THE
STUDY THAT DANIEL SEBERT DID
ONLY THEY DID IT WITH
PSYCHEDELICS SO THEY PRETREATED
HUMANS WITH KETANSERIN, AND THEN
THEY GAVE THEM A WHOPPING DOSE
OF LSD OR PSILOCYBIN AND THEY
THE EFFECTS WERE THERE WERE NO
EFFECTS.
THE PSYCHEDELIC OOSKTS WERE
TOTALLY BLOCKED.
OKAY?
AND I HAVE HEARD SUBSEQUENTLY
FROM ANECDOTAL RESPORTS WHERE
INDIVIDUALS HAVE DOSED
THEMSELVES WITH EVEN MORE
SELECTIVE 5 HT2 A ANTAGGIST AND
[INDISCERNIBLE] THAT IT'S
IDENTICAL.
IF YOU TAKE M1907 AND THEN TAKE
LSD YOU WILL NOT HAVE ANY EFFECT
OF LSD.
SO IT'S CLEAR THAT THE
PSYCHEDELIC ACTIONS ARE MEDIATED
BY THE PSYCHEDELIC RECEPTOR,
THAT WAS--AND I'M JUST GOING TO
FINISH UP HERE, I WILL NOT GO
THROUGH ALL THE SLIDES BUT I
WANT TO LEAVE TIME FOR QUESTIONS
AND THAT WAS--THAT WAS IN A WAY
THAT WAS CONVENIENT FOR ME
BECAUSE THAT WAS THE RECEPTOR I
STUDIED, SO, WHEN I BECAME A
YOUNG--ASSISTANT PROFESSOR, THE
5 HT-2 A RECEPTOR, WAS THE
RECEPTOR I DID STRUCTURE,
FUNCTION STUDIES ON, AND THIS
IS--SO DAVE WILL LIKE THIS, THIS
IS OUR MODEL OF RGOTTA MIN
VERSUS LSD BINDING THAT WE
PUBLISHED IN 1995.
AND IT TURNED OUT THIS MODEL WAS
ACTUALLY SOMEWHAT CORRECT.
I WILL JUST SAY IT WASN'T
ENTIRELY INCORRECT.
AND BUT WE WERE ULTIMATELY ABLE
TO GET THE STRUCTURE.
SO WE SAW--WE'VE SOLVED MANY,
MANY STRUCTURES OF PSYCHEDELICS,
IT'S ALL PUBLISHED DATA AND I
JUST WANT TO SHOW YOU THIS
CARTOON HERE.
SO THIS IS LSD.
ANYBODY KNOW WHAT SONG THIS IS?
THIS IS LSD, IMAGINE SOMEBODY
JUST TOOK IT AND THEY'RE IN THE
BACKGROUND IS THE 5 HT2 A
RECEPTOR, SEE IT'S DANCING
AROUND AND LSD BINDS IN A
MULTISTEP WAY TO THE RECEPTOR
THERE, YOU'LL SEE IN JUST A
MINUTE.
AND THEN A LED COMES OVER AND
THEN THE RECEPTOR IS ACTIVATED
AND NOW WE'RE GOING TO DIVE
INSIDE THE CELL HERE IN JUST A
MINUTE HERE WE GO AND THERE ARE
THE GPROTEINS, THERE'S THE ALPHA
SUBUNIT IN BLUE, AND THE BETA
GAMMA SUBUNITS, AND THIS IS THE
PSYCHEDELIC EXPERIENCE RIGHT
HERE, SEE THIS CALCIUM SPARK
THAT WE THINK, THAT WE THINK IS
THE PSYCHEDELIC EXPERIENCE, SO
WHAT THESE DRUGS DO IS THEY
CAUSE THE NEURON TO FIRE IN A
VERY IEE, AUDIENCE SYNCHRONOUS
FASHION, SO GO TO THE IN
ACCIDENT 1.
WE DON'T NEED TO SEE THAT MORE
THAN ONCE.
IT CAUSES NEURONS TO FIRE IN A
VERY ASYNCHRONOUS FASHION AND
THE NEURONS THAT ARE MADE TO
FIRE IN THIS DISORGANIZE HADED
FASHION ARE LAYER 5 PATHWAY
GIVES RAMITTAL NEURONS IN THE
CORTEX.
AND THESE RECEPTORS ARE FOUND IN
A PARTICULAR PART, THEY'RE FOUND
IN THE APICAL DENDRITE AND SO
THE APICAL DENDRITE FOR
PARAMETER NEURONS FOR THOSE WHO
ARE NOT NEUROSCIENTIST SYSTEM
EXTREMELY IMPORTANT FOR
INTEGRATING INFORMATION FROM
OTHER CORTICALE SITES AND IS
RESPONSIBLE FOR GIVING US THE
PICTURE OF REALITY THAT WE
EXPERIENCE, OKAY?
SO WHAT PSYCHEDELIC DRUGS DO IS
THEY CAUSE THIS, THEY BASICALLY
INJECT NOISE IN THE SYSTEM, AND
THE NOISE IS INTERPRETED BY THE
BRAIN AND BY YOUR THOUGHTS AS A
PSYCHEDELIC EXPERIENCE BUT IT'S
JUST NOISE.
AND IF YOU LOOK AT THIS FROM A
MACROSCALE, AS YOU IMAGINE THERE
ARE PEOPLE THAT HAVE DONE
NEUROIMAGING OF INDIVIDUALS ON
PSYCHEDELICS AND WHAT HAPPENS IS
THERE'S AN INCREASE IN BRAIN
ENTROPY OR DISORGANIZATION.
SO I KNOW I'M GOING A LITTLE
OVER TIME I AND WANT TO FINISH
WITH 1 EXPERIMENT, OKAY?
SO THE QUESTION IS: NOW THAT WE
HAVE ALPHA FOLD DO WE NEED TO
SOLVE ANY MORE STRUCTURES?
OKAY?
SO WHEN THE ALPHA FOLD PAPER
CAME OUT IT WAS HIGHLIGHTED IN
THE NEW YORK SOMETIMES AND MY
WIFE CALLED ME AND SHE SAID, DID
YOU READ ABOUT THIS?
SHE SAID YOU DON'T HAVE TO SOLVE
ANYMORE STRUCTURES EVER AGAIN.
[LAUGHTER]
I SAID YEAH, YEAH, I KNOW ABOUT
ALPHA FOLD.
SO, THIS IS UNPUBLISHED DATA SO
WE DECIDED TO DO THIS VERY
STRAIGHT FORWARD QUESTION.
SO, WE HAVE AN ALPHA FOLD MODEL
OF THE HT2 A 5 STRUCTURE WE ALSO
HAVE THE STRUCTURE OF THE 5 HT2
A RECEPTOR WHICH IS BETTER FOR
DRUG DISCOVERY?
SO TO TEST THIS HYPOTHESIS, WHAT
WE DID, WAS HE DID ULTRA LARGE,
BY WE I MEAN JK LYU, AND JK HAS
HIS OWN LAB AT ROCKEFELLER.
SO WHAT JK DID WAS USING ULTRA
LARGE SCALE DOCKING, WE DOCKED
1.6 BILLION COMPOUNDS, SO THIS
WAS A LARGE NUMBER OF COMPOUNDS
AGAINST THE MODEL OF THE 5 HT2A
RECEPTOR, AND THEN SCREEN THEM
AND TESTED THEM.
OKAY.
AND THEN WE DID THE SAME THING
AGAINST A RESTRUCTURE SO WE HAD
AN UNPUBLISHED STRUCTURE OF THE
5 HT2A RECEPTOR AND WE DID THE
EXACT SAME EXPERIMENT, OKAY?
AND THE QUESTION WAS WHICH
WORKED BETTER?
ALPHA FOLD, SO THE MODEL OR THE
STRUCTURE?
ANY GUESSES?
STRUCTURE.
THAT'S WHAT I THOUGHT.
I WAS WRONG.
SO--[LAUGHTER]
--SO ACTUALLY THEY WORKED
EQUALLY AS WELL, SO THE MODEL,
THE MODEL AND THE STRUCTURE BOTH
ENRICHED THE SAME NUMBER OF
COMPOUNDS BASICALLY, BUT SIMILAR
TO THE PAPER THAT I TALKED ABOUT
ON THE D3 RECEPTOR THE UNIVERSE
OF COMPOUNDS WAS COMPLETELY
DIFFERENT.
SO THE MODEL BASICALLY WHICH--WE
KNOW IT'S DIFFERENT FROM THE
STRUCTURE BECAUSE WE COMPARED
IT, IT'S QUITE DIFFERENT, I CAN
SHOW THE DETAILS BUT IT'S REALLY
DIFFERENT, WE THINK THE MODEL IS
ACTUALLY A STRUCTURE BUT IT'S
NOT THE STRUCTURE WE CAPTURE BY
CRYOEM BASICALLY.
AND IT URNS OUT THAT THAT
THE--SO THIS WAS OUR BEST
COMPOUND, THIS CAME FROM ALPHA
FOLD AND THIS IS A COMPOUND WITH
A--LET'S SEE 28 NANO MOLAR EC 50
AND IS COMPLETELY SELECTIVE FOR
2 A OVER 2 B AND 2 C.
OKAY?
THIS IS RIGHT OUT OF THE DOCKING
CAMPAIGN, WE HAVE A DRUG
BASICALLY.
IT HAS GOOD DRUG LIKE
PROPERTIES, ORALLY AVAILABLE, ET
CETERA, ET CETERA.
AND AS I SAID WE'RE NOW DOING
THESE ULTRA LARGE SCALE DOCKING
CAMPAIGNS WITH TRILLIONS,
TRILLIONS OF MOLECULES.
AND IT--IT'S REALLY SUCCESSFUL.
SO THAT'S ALL I WANT TO SAY, THE
NEXT FRONTIER HERE, THE NEXT
THING MY LAB IS GETTING INTO ARE
COMPLEXES, SO WE THINK THAT THE
RECEPTOR, EXISTSAs A SUPER
MOLECULAR SIGNALING COMPLEX AT
THE SYNAPSE AND WE'RE TRYING TO
UNDERSTAND WHAT THE ALL THE
COMPONENTS OF THIS ARE AND SOLVE
THE STRUCTURES AND THAT'S WHAT
WE'RE WORKING ON.
SO I WANT TO THANK YOU ALL FOR
YOUR ATTENTION.
THIS IS THE TEAM THAT DID THIS
WORK.
MANY OF THEM HAVE MOVED ON TO
LABS OF THEIR OWN, CHAN ACTUALLY
JUST MOVED OUT AS WELL
TESHANGHAI INSTITUTE OF
TECHNOLOGY.
JONATHAN FAYE VERY IMPORTANT FOR
US, I GUESS HE COLLABORATES HERE
WITH PEOPLE ON CRYOEM, NOW AT
UNIVERSITY OF MARYLAND.
BRIAN SHOICHET'S LAB, AND WE'RE
ETERNALLY GRATEFUL AND INDEBTED
TO HIS HELP AS WELL AS DAVE
NICHOLS WHO'S BEEN INSPIRING FOR
ALL THINGS PSYCHEDELIC AND OF
COURSE, THIS WORK IS FUNDED
ENTIRELY BY YOUR TAX DOLLARS AND
SO, THANK YOU FOR PAYING YOUR
TAX TAX ON TIME AND I'M HAPPY TO
ANSWER ANY QUESTIONS YOU MA I
HAVE.
SO THANK YOU.
[ APPLAUSE ]
>>THANK YOU FOR MAKING A VERY
COMPLEX TOPIC VERY
UNDERSTANDABLE AND PALLETTABLE.
PLEASE PROCEED TO THE
MICROPHONES IN THE AISLES AND
ASK A QUESTION.
IF YOU'RE ONLINE, CAN YOU PUT A
COMMENT IN THE CHAT.
OR YOU CAN YELL OUT YOUR
QUESTION.
>>SO I'M CURIOUS IN CASE OF THE
RECEPTOR YOU SHOWED IN THE END,
YOU THINK THAT THE ALPHA FOLD
CAPTURES THE STRUCTURE WHICH IS
SORT OF THE REASON FOR THE
SUCCESS OF THE PREDICTIONS.
SO FROM THE OTHER SORT OF
CAMPAIGNS THAT YOU'VE DONE, DO
YOU THINK YOU CAN GENERALIZE
THAT STATEMENT?
SO WE'VE DONE IT--SO AS CAN YOU
IMAGINE, IT WAS A HUGE AMOUNT OF
WORK SO WE DID IT WITH ANOTHER
TARGET, A NONGPCR, WE GOT THE
SAME RESULTS, BASICALLY.
THERE WAS A THIRD TARGET WE DID
NOT INTERROGATE BECAUSE THE
STRUCTURE WAS SO DIFFERENT FROM
THE ALPHA FOLD MODEL.
SO THIS WAS MRGPRX4, SO THE
ALPHA FOLD FOR THAT IS QUITE
WRONG.
THE BINDING CONTROLLER OF BANK
POCKET IS IN A DIFFERENT
ORYEBTATION AND MOST IMPORTANTLY
THE ELECTROSTATICS ARE ALL
INCORRECT.
>>I SEE.
>>SO, BUT WE THINK ACTUALLY
THIS MAY BE GENERALIZABLE AT
LEAST IN THE GPCR CAIN ACE,
YEAH, IT ACTUALLY MAY BE
GENERALLY USEFUL.
>>OKAY, THANK YOU.
>>WE WERE SURPRISED.
I BET AGAINST ALPHA FOLD, BUT
THERE YOU GO.
>>THANK YOU.
>>YEAH.
>>THIS WAS A BEAUTIFUL TALK
HERE.
I WANT TO SAY WHEN YOU SAW THE
BINDING DRUG TO THE RECEPTOR WAS
THERE ANY OPERATION TO THE
STRUCTURE?
>>THERE ISN'T.
SO THERE'S NOT SO MUCH.
THERE ARE SOME FINE DETAILS
ON--SO THE 1 WE LOOKED AT IN THE
MOST DETAIL IS THE 5 HT2A
RECEPTOR SO WE HAVE ABOUT A
DOZEN DIFFERENT STRUCTURES AND
THERE ARE SOME DIFFERENCES SO
THERE ARE--IT TURNS OUT THERE
ARE AGONISTS THAT ACTIVATE THE
RECEPTOR THAT ARE NOT
PSYCHEDELIC AND THEY
ACTUALLY--THE STRUCTURE OF THEM
IS DIFFERENT THAN THE
PSYCHEDELIC DRUGS SO WE THINK
THERE MIGHT BE SOMETHING THERE.
ONE OF THE THINGS I DIDN'T GET A
TIME TO GO INTO HERE IS WE'RE
NOW DOING A LOT OF--WE'RE TRYING
TO GET INTO BASICALLY TIME
RESOLVE CRYOEM AS WELL AS
LOOKING AT DIFFERENT STATES.
SO, I GUESS YOU DO CRYO--I DON'T
KNOW HOW MANY CRYOEM PEOPLE
THERE ARE HERE BUT 1 OF THE NICE
THINGS ABOUT CRYOEM IS THAT YOU
GET EVERY STATE THERE.
THEY'RE ALL THERE ON THE GRID
AND IT'S JUST A MATTER OF
PULLING THEM OUT, ACTUALLY.
SO HAVING LARGE ENOUGH DATA SETS
AND TRAINING TO PULL THEM OUT.
SO IT'S UNLIKE CRYSTALLOGRAPHY
WHERE EVERYTHING IS IN A
LATTICE, HERE THE INTRINSIC
FLEXIBILITY IS THERE, WE
BASICALLY JUST FREEZE IT ON A
GRID, THAT'S IT, THAT'S ALL
WE'RE DOING.
AND YOU GET A NUMBER--IS IT
POSSIBLE TO SHOW THIS SLIDE
HERE?
YEAH, HERE WE GO.
SO WE'RE USING 3D VARIABILITY
ANALYSIS, WHEN WE HAVE
SUFFICIENTLY LARGE DATA SETS,
AND THIS IS AN EXPERIMENT WE DID
OR ANALYSIS WHERE WE HAVE ALL
THESE DRUGS BOUND TO THE 5 HT2A
RECEPTORS, SOME ARE RESTING SOME
ARE PSYCHEDELIC, SOME ARE NOT
PSYCHEDELIC, AND THEN WE CAN
CREATE 123 MODELS BASED ON THE
VARIABILITY ANALYSIS FROM THE
CRYOEM DATA AND THEN WE CAN MAP
THE PRINCIPLE COMPONENTS OF THAT
INTO PRINCIPLE COMPONENT SPACE
AND TO MAKE SOMETHING VERY
COMPLICATED, NOT COMPLICATED AT
ALL, WHAT WE FIND IS EACH DRUG
STABILIZED DISTINCT
CONFIRMATIONAL ENSEMBLE AND VERY
INTERESTING.
SO, HERE--SO HERE IN RED HERE,
THIS IS BROMO LSD, SO THAT
DIFFERS FROM LSD BY A SINGLE
ATOM OF BROMINE, IT'S NOT
PSYCHEDELIC AT ALL.
YOU CAN TAKE A GRAM OF BROMINE
L, D AND YOU WILL NOT HAVE A
SINGLE PSYCHEDELIC EXPERIENCE,
AND THERE YOU CAN SEE IT'S WELL
SEPARATED BASED ON 3D ANALYSIS
AND WHEN YOU LOOK AT THE FINE
DETAILS IT REALLY BEGINS TO
BRING IN--INTO SHARP FOCUS THE
REASONS FOR THE DIFFERENCES IN
PHARMAICOLOGY.
YEAH, SO WE'RE GETTING THERE
BASICALLY.
>>THE LAST QUESTION.
MIKE?
>>THANK YOU, BRIAN GREATLY
ENJOYED THE TALK.
I WAS WONDERING IF YOU COULD
ELABORATE MORE ON BIAS AGONISTS
AND THEIR THERAPEUTIC POTENTIAL.
>>YEAH, SO I HAVE A BIASED
AGONIST THAT'S IN CLINICAL
TRIALS RIGHT NOW, IT'S IN PHASE
2, IT JUST PAST PHASE 1 SO IT'S
A 5 HT2 C AGONIST THAT IS
G-PROTEIN BIASED AND WE
ANTICIPATE THAT IT WILL BE
BETTER THAN OTHER 5 HT2 C
AGONISTS BECAUSE IT WON'T SHOW
DESENSITIZATION.
SO 1 OF THE--1 OF THE IMMEDIATE
ADVANTAGES YOU GET FROM MAKING
SAY A G-PROTEIN BIAS COMPOUND
FROM AN ARRESTIN BIAS COMPOUND
IS YOU GET RID OF
DESENSITIZATION OF TACKY FILL
AXIS INTIRELY OR TO A GREAT
EXTENT.
SO AGONISTS DON'T HAVE LESS
PROPENSITY TO LOSE THEIR POTENCY
WITH CHRONIC ADMINISTRATION,
OKAY?
THAT'S THE BIG THING.
THERE HAS, YOU KNOW FOR MANY,
MANY YEARS THERE'S BEEN THIS
IDEA THAT G-PROTEIN VERSUS
ARRESTIN IS IMPORTANT I USED TO
ENTERTAIN THAT HYPOTHESIS, I
DON'T SO MUCH ANYMORE, INSTEAD
WHAT WE'RE FOCUSING ON IS
DISTINCT G-ALPHA SUBUNITS.
SO, FOR THOSE OF YOU WHO STUDY
THE BRAIN, AND IF YOU STUDY
GI-LINKED RECEPTORS, YOU NEED TO
LOOK AT GO AND GZ.
IT TURNS OUT THAT IN THE BRAIN
THERE ARE 2 MAIN GI PROTEINS, 1
IS G. O., IT IS MAYBE 1% OF THE
WHOLE PROTEIN AT THE BRAIN, IT'S
A BAND ON AN SDSGEL, IF YOU RUN
A HOMOGINIZER ON IT YOU WILL SEE
G. O. AS A BAND AND IT'S
DIFFERENT FROM G. I. AND THEN G.
Z. IS IN THE G. O. FAMILY AND
IT'S COMPLETELY DIFFERENT FROM
G. I.
WE HAVE STRUCTURES WITH G. Z.
AND IT BINDS THE RECEPTOR IN AN
ENTIRELY DIFFERENT WAY, THE
CONEETICS OF SIGNALING ARE
DIFFERENT, IT'S NOT TOXIN, IT
HAS A VERY LONG LASTING SIGNAL
COMPARED TO GI, SO WE'RE
ACTUALLY, AND WE HAVE THIS
PAPER, JUST CAME OUT IN NATURE
WITH THE LABS SUGGESTING THAT
GZBIASED AGONISTS MAY HAVE LESS
FEWER SIDE EFFECTS THAN G. O., I
DON'T KNOW IF THAT'S--IF THAT'S
GOING TO PAN OUT OR NOT BUT IT'S
CLEAR THAT A SINGLE RECEPTOR CAN
COUPLE THE MULTIPLE G-PROTEINS
THERA NO QUESTION ABOUT THAT AND
IN MANY, MANY CASES THESE ARE
OPPOSITE CELLULAR EFFECTS, AND
SO IF YOU CAN GET A DRUG THAT
BIASES TOWARDS 1 VERSUS THE
OTHER, IT'S DEFINITELY GOING TO
BE DIFFERENT AND POTENTIALLY
BETTER SO THAT'S REALLY WHAT
WE'RE FOCUSING ON NOW.
>>THANK YOU.
>>YEAH.
>>OKAY, I WOULD LIKE TO THANK
EVERYONE FOR ATTENDING IN PERSON
AND ALL THE PEOPLE ONLINE.
I WANT TO CONGRATULATE AND THANK
BRIAN ONCE AGAIN FOR THE JOHN
DALY LECTURE.
[ APPLAUSE ]