JML Hallucinogens PDF

Chemistry and Biology of Hallucinogens
Jeffrey Lipshultz
Group Meeting
April 20, 2017
disclaimer
Don’t do illegal or unsafe drugs.

outline
Classes of hallucinogens:
5-HT2A receptor agonists

ergolines (LSD)
tryptamines (psilocybin)
phenethylamines (mescaline)
Serotonin-releasing agents
methylenedioxyphenethylamines (MDxx)
NMDA receptor antagonists
phencyclidine (PCP)
ketamine
dextromethorphan (DM)
κ-Opioid receptor agonists
salvinorin A
CB1 agonists
cannabanoids (THC)
5-HT2A receptor
Location:
cell membrane of nerve cells, widely

distributed in peripheral tissues
Endogenous ligand:
serotonin (5-HT)
Physiological processes:
neuronal excitation, learning, anxiety, attention

vasoconstriction/dilation, aggregation
inflammation, immune system (vague)

NH2
Clinical importance:
may be involved in psychosis, schizophrenia HO
antagonists/inverse agonists can be used to

treat depression, schizophrenia, and N
H
hypertension
serotonin (5-HT)
ergot alkaloids
O
Bn
N
Isolation: OH
N O NHEt
Claviceps purpurea, a fungus effecting barley, O
H
rye, and morning glory plants O Me O N NMe2
O NH
Effected systems in humans:
H
N
neurological, circulatory
NMe H
H
Toxicity:
HN
Ergotism (St. Anthony’s fire), none for LSD HN
ergotamine Dostinex (cabergoline)
migraines Parkinson’s disease
Claviceps purpurea ergot-contaminated barley ergotism, aka St. Anthony’s Fire
Jakubczyk, D.; Cheng, J. Z.; O’Connor, S. E. Nat. Prod. Rep. 2014, 31, 1328.
ergot alkaloids
O
Bn
N
Isolation: OH
N O NHEt
Claviceps purpurea, a fungus effecting barley, O
H
rye, and morning glory plants O Me O N NMe2
O OH
Effected systems in humans:
H
N
neurological, circulatory
NMe H
H
Toxicity:
HN
Ergotism (St. Anthony’s fire), none for LSD HN
lysergic acid Dostinex (cabergoline)
Parkinson’s disease
Claviceps purpurea ergot-contaminated barley ergotism, aka St. Anthony’s Fire
lysergic acid biosynthesis
PPi
Me
CO2H
DmaW
Me
HN
H 2N prenyl CO2
transferase N
Me H H 3N
Me OPP O2C Glu89
O OH
NMe
H
HN
lysergic acid
Me Me
Me Me EasE/
DmaW EasF EasC
CO2H
HN
H 2N prenyl SAM N-methyl oxidoreductase/
transferase transferase catalase
Me CO2H CO2H
HN HN
Me OPP H 2N Me NH
[O]
Me
CO2H
HN
Me NH
O OH
NMe
H
HN
lysergic acid
Me Me
Me Me EasE/
DmaW EasF EasC
CO2H
HN
H 2N prenyl SAM N-methyl oxidoreductase/
transferase transferase catalase
Me CO2H CO2H
HN HN
Me OPP H 2N Me NH
OH O Me
Me Me
H EasD H EasG H ?
NHMe NHMe NMe
NAD+ NADPH H p450
H H monooxygenase
oxidase reductase
HN HN HN
chanoclavine-I chanoclavine-I aldehyde agroclavine
O OH
OH HO O
H cloA H ? NMe
NMe NMe
p450 oxidase isomerase H
H H
HN
HN HN
lysergic acid
elymoclavine paspalic acid
lysergic acid diethylamide
O NEt2
Sandoz Laboratories, Basel, Switzerland
first synthesized from lysergic acid November
NMe
16, 1938, searching for novel analeptics
H accidentally ingested April 16, 1943

O
intentionally ingested 250 μg April 19, 1943,
HN known as “BicycleNEt
Day”
2
LSD Albert Hoffman

N
nikethamide
Last Friday, April 16, 1943, I was forced to stop my

work in the laboratory in the middle of the afternoon
and to go home, as I was seized by a peculiar
restlessness associated with a sensation of mild
dizziness. On arriving home, I lay down and sank into a
kind of drunkenness which was not unpleasant and
which was characterized by extreme activity of
imagination. As I lay in a dazed condition with my eyes
closed (I experienced daylight as disagreeably bright)
there surged upon me an uninterrupted stream of
fantastic images of extraordinary plasticity and
vividness and accompanied by an intense,
kaleidoscope-like play of colors. This condition
gradually passed off after about two hours.
Hoffman, A. The Discovery of LSD and Subsequent Investigations on Naturally Occurring Hallucinogens. In Discoveries in Biological Psychiatry. Ayd, Jr., F. J.; Blackwell, B.; J. B. Lippincott: Philadelphia, 1970.
O NEt2
NMe

HN known as “Bicycle Day”
LSD Albert Hoffman
Last Friday, April 16, 1943, I was forced to stop my

work in the laboratory in the middle of the afternoon
and to go home, as I was seized by a peculiar
restlessness associated with a sensation of mild
dizziness. On arriving home, I lay down and sank into a
kind of drunkenness which was not unpleasant and
which was characterized by extreme activity of
imagination. As I lay in a dazed condition with my eyes
closed (I experienced daylight as disagreeably bright)
there surged upon me an uninterrupted stream of
fantastic images of extraordinary plasticity and
vividness and accompanied by an intense,
kaleidoscope-like play of colors. This condition
gradually passed off after about two hours.
O NEt2
NMe

LSD Albert Hoffman
April 19, 1943: Preparation of an 0.5% aqueous solution of d-

lysergic acid diethylamide tartrate.
4:20 P.M.: 0.5 cc (0.25 mg LSD) ingested orally. The solution is
tasteless.
4:50 P.M.: no trace of any effect.
5:00 P.M.: slight dizziness, unrest, difficulty in concentration, visual
disturbances, marked desire to laugh...
At this point the laboratory notes are discontinued: The last words
were written only with great difficulty. I asked my laboratory assistant
to accompany me home as I believed that I should have a repetition
of the disturbance of the previous Friday. While we were cycling
home, however, it became clear that the symptoms were much
stronger than the first time. I had great difficulty in speaking
coherently, my field of vision swayed before me, and objects
appeared distorted like images in curved mirrors. I had the
impression of being unable to move from the spot, although my
assistant told me afterwards that we had cycled at a good pace....
Once I was at home the physician was called.
O NEt2
NMe

LSD Albert Hoffman
commercialized as Delysid in 1947, for

psychiatric use (induce model psychoses,
mental relaxation, etc)
25 μg sugar-coated tablet or 100 μg in 1mL ampule
1950s: CIA conducted Project MKULTRA to

see if LSD could be a “truth serum”
patents expired in 1963, and counterculture

use began around this time, leading to ban in
1968 in the United States
Delysid
Stoll, A.; Hoffman, A. U.S. Patent 2438259, assigned to Sandoz Ltd. https://www.erowid.org/archive/rhodium/chemistry/lsdpatent.html.
Hoffman, A. LSD – My Problem Child. http://www.psychedelic-library.org/child4.htm.
O NEt2 dosing studies indicated that 20 μg was the

threshold for physical response
at typical brain concentrations (10-20 nM), LSD

NMe should activate numerous 5-HT receptors
H
HN
LSD
Wacker, D.; Dror, R. O.; Roth, B. L. et al. Cell 2017, 168, 377.
Greiner, T.; Burch, N. R.; Edelberg, R. A.M.A. Archives NeurPsych. 1958, 79, 208.


H
X-Ray crystal structure of 5-HT2B bound to LSD
revealed key L209 residue acting as “lid”
HN
exceptionally slow dissociation t½ > 220 minutes at
LSD body temperature (37 ºC) in 5-HT2A


H
HN
simulations show L229 serves same role for 5-HT2A
LSD
body temperature (37 ºC) in 5-HT2A in [3H] studies


H
HN
simulations show L229 serves same role for 5-HT2A
LSD
body temperature (37 ºC) in 5-HT2A in [3H] studies
Woodward’s total synthesis of lysergic acid
CO2H CO2H O O
O
O Me
1. H2, Raney Ni 1. SOCl2 1. PyrHBr3, hυ
NMe
2. BzCl, NaOH 2. AlCl3 2.
70% yield 77% yield O O
N N BzN
H Bz Me
BzN
NHMe
49% yield
1. HCl, H2O
2. NaOMe, MeOH
53% yield
O OH CN OH O
Cl
NMe 1. H2SO4 NMe 1. SOCl2 NHMe 1. Ac2O NMe
H H H H
2. KOH; Raney Ni 2. NaCN, HCN 2. NaBH4;
Na3AsO4•H2O 54% yield HCl
HN AcN AcN 57% yield HN
16% yield
lysergic acid
Kornfeld, E. C.; Fornefeld, E. J.; Kline, G. B.; Mann, M. J.; Morrison, D. E.; Jones, R. G.; Woodward, R. B. J. Am. Chem. Soc. 1956, 78, 3087.
Kornfeld, E. C.; Fornefeld, E. J.; Kline, G. B.; Mann, M. J.; Jones, R. G.; Woodward, R. B. J. Am. Chem. Soc. 1954, 76, 5256.
tryptamines
O Me Me
H Me
NH2 N N Me
P
HO O
O
HO HO
N N N
H H H
serotonin (5-HT) psilocybin bufotenin
many naturally-occuring tryptamines, with common biosynthetic pathways:

R
NH2 NH2 N R
CO2H
RO
N N N
H H H
tryptophan tryptamine hallucinogen

psilocybin
O Me
H Me
N
P
HO O
O
N
H
psilocybin
isolated by Hoffman from Psilocybe

mexicana (1957)
synthesized by Hoffman (1958)
commercialized by Sandoz (Indocybin)
4-10 mg dose, ~ 50-300 mg/kg
Passie, T.; Seifert, J.; Schneider, U.; Emrich, H. M. Addiction Bio. 2002, 7, 357.
psilocybin
OH
Me HO OH
Me Me
O H Me N Me
N N Me
P OH HO
HO O O O
O
alkaline phosphatase O
N
N H N
H H
psilocin psilocin O-glucoronide

psilocybin
pharmacologically active excreted in urine
isolated by Hoffman from Psilocybe

mexicana (1957) monoamine oxidase
synthesized by Hoffman (1958)
commercialized by Sandoz (Indocybin)
O
4-10 mg dose, ~ 50-300 mg/kg
OH OH R
N N
H H
4-hydroxyindole-3-acetaladehyde R = CH2OH, 4-hydroxytrypophol

R = CO2H, 4-hydroxyindole-3-acetic acid
Passie, T.; Seifert, J.; Schneider, U.; Emrich, H. M. Addiction Bio. 2002, 7, 357.
tryptamine pharmacokinetics
Me
N Me NH2
Me
N N
H H
N,N-dimethyltryptamine (DMT) α-methyltryptamine (AMT)

inactive orally effects last up to 12 hours
effects clear very quickly α-Me slows MAO activity
“businessman’s trip”
MAO-A is a flavin oxidase, which was

targeted for depression, is currently
targeted for Parkinson’s disease
Wilcox, J. J. Pscyhoactive Drugs 2012, 44, 274.

Kaplan, J.; Mandel, L. R.; Stillman, R.; Walker, R. W.; VandenHeuvel, W. J. A.; Gillin, J. C.; Wyatt, R. J. Psychopharmacologia 1974, 38, 239.
Me
N Me NH2
Me
N N
H H
N,N-dimethyltryptamine (DMT) α-methyltryptamine (AMT)

inactive orally effects last up to 12 hours
effects clear very quickly α-Me slows MAO activity
“businessman’s trip”
Ayahuasca (Amazonian spiritual medicine)
combine Psychotria viridis (DMT) and
Banisteriopsis caapi (harmine)
combine with harmine
(selective MAO-A inhibitor)
Ott found activity threshold to be
120 mg harmine, 20-30 mg DMT
MeO N
N
H Me
~ 160 mg harmine, 30 mg DMT
Ott, J. J. Psychoative Drugs 1999, 31, 171.

Wilcox, J. J. Pscyhoactive Drugs 2012, 44, 274.
Kaplan, J.; Mandel, L. R.; Stillman, R.; Walker, R. W.; VandenHeuvel, W. J. A.; Gillin, J. C.; Wyatt, R. J. Psychopharmacologia 1974, 38, 239.
Me Me
N Me N Me
MeO CYP2D6 HO
N N
H H
5-OMe-dimethyltryptamine bufotenine both found in numerous sources, including

the skin of the Colorado River Toad
dose with 5-OMe-DMT pre-treat with MAOI dose with 5-OMe-DMT-d4
Me
N Me
D
D
D
RO D
N
H
5-OMe-DMT-d4
Halberstadt, A. L.; Nichols, D. E.; Geyer, M. A. Psychpharma. 2012, 221, 709.

Shen, H.-W.; Wu, C.; Jiang, X.-L.; Yu, A.-M. Biochem. Pharma. 2010, 80, 122.
Ott, J. J. Psychoactive Drugs 2011, 33, 273.
phenethylamines
NH2
MeO NH2
HO
MeO
N
H OMe
serotonin (5-HT) mescaline

peyote (Lophophora williamsii)
very few (only one?) naturally occurring hallucinogenic phenethylamines

(they’re mostly stimulants, not hallucinogens)
O
MeO NH2 NH2
Me
Br OMe Br
O
2C-B Bromo-DragonFLY
OMe
NH2
MeO NH2
Me
X
Br OMe
OMe
X = Br, DOB TCB-2

X = I, DOI
mescaline biosynthesis
L-tyr
CO2H decarboxylase NH2
NH2 PLP
HO decarboxylase HO
tyrosine non-heme Fe2+ monophenol Cu-containing

hydroxylase monooxygenase monooxygenase monooxygenase
peyote (Lophophora williamsii)
DOPA
HO CO2H HO NH2 MeO NH2
decarboxylase COMT
NH2 PLP SAM methyl
HO decarboxylase HO transferase HO
unknown hydroxlyase
MeO NH2 MeO NH2 MeO NH2

COMT GOMT
HO SAM methyl HO SAM methyl MeO

transferase transferase
OH OMe OMe
mescaline
Rosengarten, H.; Friedhoff, A. J. Schizo. Bull. 1976, 2, 90.
Lundstrom, J. Acta Chem. Scand. 1971, 25, 3489.
Lundstrom, J.; Agurell, S. Tetrahedron Lett. 1969, 10, 3371.
mescaline pharmacokinetics
[14C]mescaline in humans
NH2 RO NH2
MeO
CYP2D6
MeO RO
OMe OR
mescaline desmethylmescaline
R = H, Me
MAO
t½ ~ 6 hours
MeO OH
O significantly less potent than LSD, psilocin

MeO
OMe
3,4,5-trimethoxyphenyl acetic acid
Nichols, D. E. Pharmacol. Ther. 2004, 101, 131.

Hermle, L. et al. Biol. Psych. 1992, 32, 976.
Charalampous, K. D.; Walker, K. E.; Kinross-Wright, J. Psychopharmacologia 1966, 9, 48.
Wu, D.; Otton, S. V.; Inaba, T.; Kalow, W.; Sellers, E. M. Biochem. Pharma. 1997, 53, 1605.
synthetic phenethylamines
OMe OMe
MeO NH2 NH2 NH2
Me
MeO Br Br
OMe OMe OMe
mescaline 2C-B DOB

200-400 mg 5-25 mg 0.2-2 mg
OMe OMe
NH2 NH2
Me Me
[125I] I
OMe OMe
[125I]DOI DOI
0.5-3 mg
highly selective 5-HT2 ligand
Ki = 0.7-20 nM (5-HT2)
Ki > 1000 nM (5-HT1, 5-HT5)
McKenna, D. J.; Nazarali, A. J.; Hoffman, A. J.; Nichols, D. E.; Mathis, C. A.; Saavedra, J. M. Brain Research 1989, 476, 45.
Charalampous, K. D.; Walker, K. E.; Kinross-Wright, J. Psychopharmacologia 1966, 9, 48.
Shulgin, A.; Shulgin, A. PiHKAL: A Chemical Love Story 1991.
constrained mescaline analogues
MeO NH2 MeO NH2 MeO

vs.
NH2
MeO MeO MeO
MeO MeO OMe
mescaline transoid mescaline cisoid mescaline

40 mg/kg 20 mg/kg 160 mg/kg
could constraining the alkylamino chain

lead to increased potency?
Cooper, P. D.; Walters, G. C. Nature 1972, 238, 96.

OMe OMe O O
NH2 NH2 NH2 NH2
Me Me Me Me
Br Br Br Br
OMe O O O
DOB Bromo-DragonFLY
Ki = 2.6 nM for 5-HT2 Ki = 3.1 nM for 5-HT2 Ki = 1.2 nM for 5-HT2A Ki = 0.31 nM for 5-HT2A
ED50 = 250 nmol/kg ED50 = 570 nmol/kg ED50 = 61 nmol/kg ED50 = 22 nmol/kg
O NEt2
NMe
H
HN
LSD
ED50 = 40 nmol/kg
Chambers, J. J.; Kurrasch-Orbaugh, D. M.; Parker, M. A.; Nichols, D. E. J. Med. Chem. 2001, 44, 1003.
Chambers, J. J.; Kurrasch-Orbaugh, D. M.; Parker, M. A.; Nichols, D. E. J. Med. Chem. 2001, 44, 1003.
Parker, M. A.; Marona-Lewicka, D.; Lucaites, V. L.; Nelson, D. L.; Nichols, D. E. J. Med. Chem. 1998, 41, 5148.
Monte, A. P.; Marona-Lewicka, D.; Parker, M. A.; Wainscott, D. B.; Nelson, D. L.; Nichols, D. E. J. Med. Chem. 1996, 2953.
Nichols, D. E.; Snyder, S. E.; Oberlender, R.; Johnson, M. P.; Huang, X. J. Med. Chem. 1991, 34, 276.
NH2
MeO NH2
MeO
MeO
MeO
OMe
OMe
mescaline Jimscaline
Ki = 360 nM for 5-HT2A Ki = 69 nM for 5-HT2A
EC50 = 113000 nM EC50 = 3200 nM
McLean, T. H.; Parrish. J. C.; Braden, M. R.; Marona-Lewicka, D.; Gallardo-Godoy, A.; Nichols, D. E. J. Med. Chem. 2006, 49, 5794.
McLean, T. H.; Chambers, J. J.; Parrish. J. C.; Braden, M. R.; Marona-Lewicka, D.; Kurrasch-Orbaugh, D.; Nichols, D. E. J. Med. Chem. 2006, 49, 4269.
Chambers, J. J.; Nichols, D. E. J. Comp.-Aid. Mol. Des. 2002, 16, 511.
NH2
MeO NH2
MeO
MeO
MeO
OMe
OMe
mescaline Jimscaline
Ki = 360 nM for 5-HT2A Ki = 69 nM for 5-HT2A
EC50 = 113000 nM EC50 = 3200 nM
O NEt2
OMe OMe NH2 OMe

NH2 NH2 NMe
H
Br Br Br
OMe OMe OMe HN
2C-B 2CB-Ind TCB-2 LSD

Ki = 0.88 nM for 5-HT2A Ki = 47 nM for 5-HT2A Ki = 0.26 nM for 5-HT2A Ki = 3.5 nM for 5-HT2A
EC50 = 27 nM EC50 = 18 nM EC50 = 9.8 nM
McLean, T. H.; Parrish. J. C.; Braden, M. R.; Marona-Lewicka, D.; Gallardo-Godoy, A.; Nichols, D. E. J. Med. Chem. 2006, 49, 5794.
McLean, T. H.; Chambers, J. J.; Parrish. J. C.; Braden, M. R.; Marona-Lewicka, D.; Kurrasch-Orbaugh, D.; Nichols, D. E. J. Med. Chem. 2006, 49, 4269.
Chambers, J. J.; Nichols, D. E. J. Comp.-Aid. Mol. Des. 2002, 16, 511.
serotonin-releasing agents
O NHMe
Me dubbed empathogen (generating a state of empathy)

O
- Metzner and Nichols, 1983-84
3,4-methylenedioxymethamphetamine renamed as entactogen (touching within)
(MDMA, ecstasy) -Nichols, 1986
first synthesized in 1912 by Merck KGaA
O Me
O 1. HBr O NH2 O NHMe
NMe
O
O 2. NH3 O
Me
O
Me
OH
safrole safrylamine safrylmethylamine 3-methylhydrastinine

(MDA) (MDMA)
first studied in animals in the 1950s at University increased serotonin release,

of Michigan, commissioned by the US Army combined with reuptake inhibition
synthesized by Shulgin in 1965 at Dow, not tested acute toxicity at high doses due to
serotonin syndrome – increased heart
confirmed to be in use in Chicago in 1970 rate, blood pressure, body
temperature, tremors, hallucinations
Shulgin and Nichols publish first report of MDMA’s
effect on humans in 1978
Benzenhofer, U.; Passie, T. Addiction 2010, 105, 1355.

Hardman, H. F.; Haavik, C. O.; Seevers, M. H. Toxicol. Appl. Pharmacol. 1973, 25, 299.
Nichols, D. E. J. Psychoactive Drugs 1986, 18, 305.
MDMA metabolism and pharmacokinetics
NHMe NH2 HO NH2

O CYP3A4 O CYP2D6
Me Me Me
O N-demethylation O demethylenation HO
MDMA MDA HHA
24% 2% <1%
COMT
CYP2D6
tmax ~ 2h, t½ ~ 8-9 h SAM methyl
demethylenation
transferase
HO NHMe MeO NHMe MeO NH2

COMT CYP??
Me Me Me
HO SAM methyl HO N-demethylation HO
HHMA transferase HMMA HMA
<1% 17% 2%
MDMA HMMA
de la Torre, R. et al. Annal. NY Acad. Sci. 2000, 914, 225.

de la Torre, R. et al. Br. J. Clin. Pharmacol. 1999, 49, 104.
de la Torre, R. et al. J. Anal. Toxicol. 2002, 26, 157.
4-MTA
O NHMe NH2 NH2
Me Me Me
O MeS Cl
MDMA 4-methylthioamphetamine p-chloroamphetamine

(MTA) (PCA)
ED50 = 2.79 μmol/kg ED50 = 0.95 μmol/kg ED50 = 0.84 μmol/kg
IC50 (nM) to inhibit uptake
[3H]serotonin 74 182
MTA’s serotonin-selective uptake
inhibition should make it a more [3H]dopamine 3073 424
effective tool compound than PCA
[3H]norepinephrine 2375 207
“I was particularly disturbed to see my name in the article, and that I had been
‘especially valuable’ to their cause [of preparing designer drugs]… Without my
knowledge, MTA was synthesized by others and made into tablets call, appropriately
illicit production and distribution enough, ‘flatliners’. Some people who took them died… It not only caused the release
lead to several deaths in Europe in of serotonin from neurons, but also prevented the breakdown of this neurotransmitter…
the early 2000’s I had published information that had ultimately lead to human death… I strive to find
positive things, and when my research is used for negative ends it upsets me… This
question, which was never part of my research focus, now haunts me.”
Nichols, D. E. Nature 2011, 469, 7.

Huang, X.; Marona-Lewicka, D.; Nichols, D. E. Eur. J. Pharmacol. 1992, 229, 31.
NMDA receptor
Location:
ion channel protein in nerve cells O

HO
OH
Endogenous ligands:
O NHMe
glutamate and glycine
N-methyl-D-asparate is a specific
agonist, mimicking glutamate
synaptic plasticity (learning, memory)
Ca2+, Na+ into cell, K+ out of cell
age-related memory loss

OH O
potentially Alzheimer’s disease
alcohol withdrawal NH2 Me NH2

Me O O NH
partial agonism of glycine site allosetric site O
has led to breakthrough antidepressants, OH N
namely Rapastinel (Allergan) N
Rapastinel
Moskal, J. R. et al. Neuropharmacol. 2005, 49, 1077.
Mishina, M. et al. Nature 1992, 358, 36.
MacDermott, A. B.; Mayer, M. L.; Wetbrook, G. L.; Smith, S. J.; Barker, J. L. Nature 1986, 321, 519.
NMDAR antagonists (dissociatives)
OMe
Me Et
O O
HN HN
N
H
N
Me Cl OMe
phencyclidine dextromethorphan ketamine methoxetamine

(PCP) (DXM, DM) (MXE)
first synthesized by Parke- first synthesized by Hoffman first synthesized by Parke- first synthesized in 2010 by
Davis in 1956 -La Roche in 1947 Davis in 1962 www.bluelight.ru users
FDA approved anaesthetic in FDA approved OTC FDA approved anaesthetic in “designer” drug
1957, marketed as Sernyl antitussive, as Romilar 1969, marketed as Ketalar
pulled in 1965 due to adverse
behavioral effects
Morris, H.; Wallach, J. Drug Test. Analysis 2014, 6, 614.

ketamine pharmacology
Me Me
O O O
HN HN NH2
CYP2B6
N-demethylation
Cl Cl Cl
ketamine (S)-ketamine norketamine

~ 4x more active than (R) detectable in plasma
0.5–1 mg/kg for 2-3 min after IV
general anaesthesia
20-80 μM [ketamine] 300-850 μM [ketamine]
CYP2B6
inhibitors
CYP3A4
inhibitors
Li, Y. et al. Drug Metab. Dispos. 2013, 41, 1264.

Mion, G.; Villevieille, T. CNS Neurosci. Ther. 2013, 19, 370.
ketamine pharmacology
Me Me
O O O
HN HN NH2
CYP2B6
N-demethylation
Cl Cl Cl
ketamine (S)-ketamine norketamine

~ 4x more active than (R) detectable in plasma
0.5–1 mg/kg for 2-3 min after IV
general anaesthesia
(S)-ketamine clearance > (R)-ketamine clearance (R)-ketamine inhibits (S)-ketamine clearance

21.3 mL/kg min 17.4 mL/kg min
White, P. F.; Schuttler, J.; Shafer, A.; Stanski, D. R.; Horai, Y.; Trevor, A. J. Br. J. Anaesth. 1985, 57, 197.
Ihmsen, H.; Geisslinger, G.; Schuttler, J. Clin. Pharmacol. Ther. 2001, 70, 431.
Mion, G.; Villevieille, T. CNS Neurosci. Ther. 2013, 19, 370.
ketamine psychadelic effects
Me
O general anesthesia plasma level:
HN 600 – 1100 ng/mL
adminstered plasma level:
50 – 200 ng/mL
analgesic plasma level:
100 – 200 ng/mL
Cl
ketamine
Bowdle, T. A. et al. Anaesth. 1998, 88, 82.

development of methoxetamine
Me Me
O Me H O
HN N N HN
Cl OMe
ketamine PCP PCE methoxetamine

10–250 mg “more active than PCP” 10–100 mg
<30 min onset 30–90 min onset
<3 h duration 5–7 h duration
“3-MeO-PCP and 3-MeO- “At long last I eventually

PCE are simply incredible Me H got to try the title
N OMe N OMe
drugs. They have a true compound and oh was it
capacity for healing… At 15 worth waiting for. Imagine a
mg, I felt 3-MeO-PCP was dissociative state, with the
possibly the most amazing scary bits removed and
drug I had ever consumed, less confusion… this is the
and 3-MeO-PCE seemed perfumed garden, the
to have the full capacity to 3-OMe-PCP 3-OMe-PCE sirens singing… less freaky
be the next LSD.” “extrememly similar to PCP “extrememly similar to PCP and absolute bliss.”
-M in potency and quality” in potency and quality” - fastandbulbous

Corazza, O.; Assi, S.; Schifano, F. CNS. Neurosci. Ther. 2013, 19, 454.
Corazza, O. et al. Hum. Psychopharmacol. Clin. Exp. 2012, 27, 145.
Morris, H. Interview with a Ketamine Chemist. https://www.vice.com/en_us/article/interview-with-ketamine-chemist-704-v18n2
development of methoxetamine
Me Me
O Me H O
HN N N HN
Cl OMe
ketamine PCP PCE methoxetamine

10–250 mg “more active than PCP” 10–100 mg
<30 min onset 30–90 min onset
<3 h duration 5–7 h duration
“3-MeO-PCP and 3-MeO- “At long last I eventually

PCE are simply incredible Me H got to try the title
N OMe N OMe
drugs. They have a true compound and oh was it
capacity for healing… At 15 worth waiting for. Imagine a
mg, I felt 3-MeO-PCP was dissociative state, with the
possibly the most amazing scary bits removed and
drug I had ever consumed, less confusion… this is the
and 3-MeO-PCE seemed perfumed garden, the
to have the full capacity to 3-OMe-PCP 3-OMe-PCE sirens singing… less freaky
be the next LSD.” “extrememly similar to PCP “extrememly similar to PCP and absolute bliss.”
-M in potency and quality” in potency and quality” - fastandbulbous

Corazza, O.; Assi, S.; Schifano, F. CNS. Neurosci. Ther. 2013, 19, 454.
Corazza, O. et al. Hum. Psychopharmacol. Clin. Exp. 2012, 27, 145.
Morris, H. Interview with a Ketamine Chemist. https://www.vice.com/en_us/article/interview-with-ketamine-chemist-704-v18n2
κ-Opioid Receptor
Location:
cell membrane of nerve cells, in HN NH2 HN NH2
brain and spinal cord NH NH H 2N
O O O
H H H
O N N N N
Endogenous ligand: N
H
O
N
H
O
N
H
O NH H
O OH
NH Me O N N
H O
dynorphins O
HN O
HN
NH
NH2
H 2N
O
H 2N
dynorphin A
OH
pain
consciousness
addiction
HO
MeO
targeted for analgesic effects OH
O N
potentially a natural addiction O H Et
N
control mechanism
N
N H
O Me
nalfurafine ibogaine
antipruritic (anti-itch) anti-addiction and hallucinogen
Alper, K. R. et al. Am. J. Addict. 1999, 8, 234.

Vastag, B. Science 2005, 308, 345.
salvinorin A
O O
H H
AcO
O
Me
Me
O OMe
salvinorin A
isolated from Salvia
divinorum in 1982
dose (smoked): 200–500 μg

O O duration: < 1 hour
H H Ki = 2.4 nM, EC50 = 1.8 nM
O
R O for κ-opioid receptor
Me
Me
O OMe
Prisinzano, T. E.; Rothman, R. B. Chem. Rev. 2008, 108, 1732.
Cohen, B. et al. Bioorg. Med. Chem. 2005, 13, 5635.
Prisinzano, T. E. Life Sci. 2005, 78, 527.
MacLean, K. A. et al. Psychopharmacol. 2013, 226, 381.
Roth, B. L. et al. J. Pharmacol. Exp. Ther. 2004, 308, 1197.
Roth, B. L. et al. Proc. Nat. Acad. Sci. 2002, 99, 11934.
biosynthesis and total synthesis of salvinorin A
OPP OPP OPP
Me Me Me
Me Me SdCPS2 H
Me Me Me
H H Me
H H
Me
Me Me Me Me Me
oxidations
O
O
O
O Me
BOMO O O
TBAF H O O
O BOMO H H
Me O AcO
O
99% Me O
O Me
OH
MeO OMe Me
Me
MeO OMe
O OMe
salvinorin A
Scheerer, J. R.; Lawrence, J. F.; Wang, G. C.; Evans, D. A. J. Am. Chem. Soc. 2007, 129, 8968.
Zerbe, P. Plant Journal 2017, 89, 885.
Kutrzeba, L.; Dayan, F. E.; Howell, J.; Feng, J.; Giner, J.-L.; Zjakiony, J. K. Phytochem. 2007, 68, 1872.
CB1 receptor
H 2N
Location: O
nerve cell membrane receptors, O

primarily in brain and spinal cord Me
Endogenous ligands: O-arachidonoylethanolamine

(virodhamine)
arachidonic acid derivatives
antagonist
Physiological processes: HO
O
pain, mood, memory
O
appetite
Me
OH
2-arachidonoylglycerol (2-AG)
substance abuse agonist
obesity
Me
O
OH
H
H N
Me O n-pent n-pent
Me
Δ9-tetrahydrocannabinol (THC) JWH-018
Janero, D. R.; Makriyannis, A. Exp. Op. Emerg. Drugs 2009, 14, 43.
Pertwee, R. G. et al. Pharmacol. Rev. 2010, 62, 588.
CB1 receptor
Location:
nerve cell membrane receptors,

primarily in brain and spinal cord
Endogenous ligands:
pain, mood, memory

appetite
substance abuse
obesity
Shao, Z.; Yin, J.; Chapman, K.; Grzemska, M.; Clark, L.; Wang, J.; Rosenbaum, D. M. Nature 2016, 540, 602.
CB1 receptor
Location:
nerve cell membrane receptors,

primarily in brain and spinal cord
Endogenous ligands:
pain, mood, memory

appetite
substance abuse
obesity
Shao, Z.; Yin, J.; Chapman, K.; Grzemska, M.; Clark, L.; Wang, J.; Rosenbaum, D. M. Nature 2016, 540, 602.
tetrahydrocannabinol metabolism
HO
Me CO2H
OH OH OH
H CYP2C9 H H
H
allylic H
oxidation H
hydroxylation
Me O n-pent Me O n-pent Me O n-pent
Me Me Me
THC 11-OH-THC THC-CO2H

active metabolite inactive metabolite
CYP3A4 t½ (urine) = 3-4 days
allylic
hydroxylation
HO
Me
HO HO
OH OH
H H
H allylic H
hydroxylation
Me O n-pent Me O n-pent
Me Me
8-OH-THC 8,11-di-OH-THC
Huestis, M. A. Handb. Exp. Pharmacol. 2005, 168, 657.

tetrahydrocannabinol metabolism
HO
Me CO2H
OH OH OH
H CYP2C9 H H
H
allylic H
oxidation H
hydroxylation
Me O n-pent Me O n-pent Me O n-pent
Me Me Me
THC 11-OH-THC THC-CO2H

active metabolite inactive metabolite
CYP3A4 t½ (urine) = 3-4 days
allylic
hydroxylation
HO
Me
HO HO
OH OH
H H
H allylic H
hydroxylation
Me O n-pent Me O n-pent
Me Me
8-OH-THC 8,11-di-OH-THC
Huestis, M. A. Handb. Exp. Pharmacol. 2005, 168, 657.

synthetic cannabinoids
Me
O O
OH
H
H
N N
Me O n-pent
Me n-pent n-Bu
THC JWH-018 JWH-073
Ki (CB1) = 41 nM Ki (CB1) = 9 nM Ki (CB1) = 8.9 nM Prof. John Huffman
Ki (CB2) = 36 nM Ki (CB2) = 2.9 nM Ki (CB2) = 38 nM Clemson
OH
O
OH
H
H
n-hex N
Me O
Me
Me Me
HU-210 AM-2201
Ki (CB1) = 234 pM Ki (CB1) = 1 nM F
Ki (CB2) = 36 nM Ki (CB2) = 2.6 nM
Kassiou, M. et al. ACS Chem. Neurosci. 2015, 6, 1445.
Mechoulam, R. et al. Neuropharmacol. 1990, 29, 161.
Devane, W. A.; Mechoulam, R. et al. J. Med. Chem. 1992, 35, 2065.
Huffman, J. W. et al. Br. J. Pharmacol. 2010, 160, 585.
McCoy, T. How this chemist unwittingly helped spawn the synthetic drug industry. Washington Post, Huffman, J. W. et al. Bioorg. Med. Chem. 2005, 13, 89.
2015. http://wapo.st/1MeUthy Huffman, J. W. et al. J. Pharmacol. Exp. Ther. 1998, 285, 995.
Wang, L. John W. Huffman. C&EN, 2010. http://cen.acs.org/articles/88/i26/John-W-Huffman.html Seely, K. A.; Lapoint, J.; Moran, J. H.; Fattore, L. Prog. Neuro-Psychopharmacol. Biol. Psych. 2012, 39, 234.
“Taking LSD was a profound experience, one “How long will this last, this delicious feeling of
of the most important things in my life. LSD being alive, of having penetrated the veil which
shows you that there’s another side to the hides beauty and the wonders of celestial vistas?
coin, and you can’t remember it when it wears It doesn't matter, as there can be nothing but
off, but you know it. It reinforced my sense of gratitude for even a glimpse of what exists for
what was important—creating great things those who can become open to it.”
instead of making money, putting things back
into the stream of history and of human “Our entire universe is contained in the mind and
consciousness as much as I could.” the spirit. We may choose not to find access to it,
– Steve Jobs we may even deny its existence, but it is indeed
there inside us…”
“I was completely astonished by the beauty – Alexander Shulgin
of nature. Our eyes see just a small fraction
of the light in the world. It is a trick to make a
colored world, which does not exist outside
of human beings.” "Hallucinogens have a unique and powerful ability
– Albert Hofmann to affect the human psyche. They may alter one's
concepts of reality, may change one's views on
Picture yourself in a boat on a river life and death, and can provoke and challenge
With tangerine trees and marmalade skies one's most cherished beliefs. Therein...lay the
Somebody calls you, you answer quite slowly roots of much of the fear and hysteria that these
A girl with kaleidoscope eyes substances have fostered in our society."
– David. E. Nichols
Cellophane flowers of yellow and green
Towering over your head
Look for the girl with the sun in her eyes
And she's gone “LSD is a psychedelic drug which occasionally
causes psychotic behavior in people who have
Lucy in the sky with diamonds NOT taken it.”
– The Beatles – Timothy Leary
“Taking LSD was a profound experience, one “How long will this last, this delicious feeling of
of the most important things in my life. LSD being alive, of having penetrated the veil which
shows you that there’s another side to the hides beauty and the wonders of celestial vistas?
coin, and you can’t remember it when it wears It doesn't matter, as there can be nothing but
off, but you know it. It reinforced my sense of gratitude for even a glimpse of what exists for
what was important—creating great things those who can become open to it.”
instead of making money, putting things back
into the stream of history and of human “Our entire universe is contained in the mind and
consciousness as much as I could.” the spirit. We may choose not to find access to it,
– Steve Jobs we may even deny its existence, but it is indeed
there inside us…”
“I was completely astonished by the beauty – Alexander Shulgin
of nature. Our eyes see just a small fraction
of the light in the world. It is a trick to make a
colored world, which does not exist outside
of human beings.” "Hallucinogens have a unique and powerful ability
– Albert Hofmann to affect the human psyche. They may alter one's
concepts of reality, may change one's views on
Picture yourself in a boat on a river life and death, and can provoke and challenge
With tangerine trees and marmalade skies one's most cherished beliefs. Therein...lay the
Somebody calls you, you answer quite slowly roots of much of the fear and hysteria that these
A girl with kaleidoscope eyes substances have fostered in our society."
– David. E. Nichols
Cellophane flowers of yellow and green
Towering over your head
Look for the girl with the sun in her eyes
And she's gone “LSD is a psychedelic drug which occasionally
causes psychotic behavior in people who have
Lucy in the sky with diamonds NOT taken it.”
– The Beatles – Timothy Leary

JML Hallucinogens PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

JML Hallucinogens PDF

Uploaded by

Copyright:

Available Formats

Chemistry and Biology of Hallucinogens

Don’t do illegal or unsafe drugs.

5-HT2A receptor agonists

cell membrane of nerve cells, widely

neuronal excitation, learning, anxiety, attention

inflammation, immune system (vague)

may be involved in psychosis, schizophrenia HO

antagonists/inverse agonists can be used to

Claviceps purpurea ergot-contaminated barley ergotism, aka St. Anthony’s Fire

Claviceps purpurea ergot-contaminated barley ergotism, aka St. Anthony’s Fire

Me OPP O2C Glu89

chanoclavine-I chanoclavine-I aldehyde agroclavine

H accidentally ingested April 16, 1943

LSD Albert Hoffman

Last Friday, April 16, 1943, I was forced to stop my

H accidentally ingested April 16, 1943

intentionally ingested 250 μg April 19, 1943,

Last Friday, April 16, 1943, I was forced to stop my

H accidentally ingested April 16, 1943

intentionally ingested 250 μg April 19, 1943,

April 19, 1943: Preparation of an 0.5% aqueous solution of d-

H accidentally ingested April 16, 1943

intentionally ingested 250 μg April 19, 1943,

commercialized as Delysid in 1947, for

25 μg sugar-coated tablet or 100 μg in 1mL ampule

1950s: CIA conducted Project MKULTRA to

patents expired in 1963, and counterculture

O NEt2 dosing studies indicated that 20 μg was the

at typical brain concentrations (10-20 nM), LSD

O NEt2 dosing studies indicated that 20 μg was the

at typical brain concentrations (10-20 nM), LSD

O NEt2 dosing studies indicated that 20 μg was the

at typical brain concentrations (10-20 nM), LSD

O NEt2 dosing studies indicated that 20 μg was the

at typical brain concentrations (10-20 nM), LSD

NMe 1. H2SO4 NMe 1. SOCl2 NHMe 1. Ac2O NMe

many naturally-occuring tryptamines, with common biosynthetic pathways:

tryptophan tryptamine hallucinogen

isolated by Hoffman from Psilocybe

psilocin psilocin O-glucoronide

isolated by Hoffman from Psilocybe

4-hydroxyindole-3-acetaladehyde R = CH2OH, 4-hydroxytrypophol

N,N-dimethyltryptamine (DMT) α-methyltryptamine (AMT)

MAO-A is a flavin oxidase, which was

Wilcox, J. J. Pscyhoactive Drugs 2012, 44, 274.

N,N-dimethyltryptamine (DMT) α-methyltryptamine (AMT)

Ott, J. J. Psychoative Drugs 1999, 31, 171.

5-OMe-dimethyltryptamine bufotenine both found in numerous sources, including

dose with 5-OMe-DMT pre-treat with MAOI dose with 5-OMe-DMT-d4

Halberstadt, A. L.; Nichols, D. E.; Geyer, M. A. Psychpharma. 2012, 221, 709.

serotonin (5-HT) mescaline

very few (only one?) naturally occurring hallucinogenic phenethylamines

X = Br, DOB TCB-2

tyrosine non-heme Fe2+ monophenol Cu-containing

MeO NH2 MeO NH2 MeO NH2

HO SAM methyl HO SAM methyl MeO

O significantly less potent than LSD, psilocin

3,4,5-trimethoxyphenyl acetic acid

Nichols, D. E. Pharmacol. Ther. 2004, 101, 131.

mescaline 2C-B DOB

MeO NH2 MeO NH2 MeO

mescaline transoid mescaline cisoid mescaline

could constraining the alkylamino chain