Chemistry and Biology of Hallucinogens

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Jeffrey Lipshultz Group Meeting April 20, 2017 Chemistry and Biology of Hallucinogens disclaimer

Don’t do illegal or unsafe drugs. Chemistry and Biology of Hallucinogens 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) Chemistry and Biology of Hallucinogens

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 hypertension H serotonin (5-HT) Chemistry and Biology of Hallucinogens ergot alkaloids O Bn N Isolation: OH N O NHEt O Claviceps purpurea, a fungus effecting barley, 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. Chemistry and Biology of Hallucinogens ergot alkaloids O Bn N Isolation: OH N O NHEt O Claviceps purpurea, a fungus effecting barley, 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

Jakubczyk, D.; Cheng, J. Z.; O’Connor, S. E. Nat. Prod. Rep. 2014, 31, 1328. Chemistry and Biology of Hallucinogens lysergic acid biosynthesis

PPi

Me DmaW CO2H Me HN H N prenyl CO 2 transferase N 2 Me H H3N

Me OPP O2C Glu89

O OH

NMe H

HN lysergic acid Jakubczyk, D.; Cheng, J. Z.; O’Connor, S. E. Nat. Prod. Rep. 2014, 31, 1328. Chemistry and Biology of Hallucinogens lysergic acid biosynthesis

Me Me

Me Me EasE/ DmaW EasF EasC CO2H HN H N prenyl SAM N-methyl oxidoreductase/ 2 transferase transferase catalase Me CO2H CO2H HN HN Me OPP H2N Me NH

[O]

CO2H HN Me NH

O OH

NMe H

HN lysergic acid Jakubczyk, D.; Cheng, J. Z.; O’Connor, S. E. Nat. Prod. Rep. 2014, 31, 1328. Chemistry and Biology of Hallucinogens lysergic acid biosynthesis

Me Me

Me Me EasE/ DmaW EasF EasC CO2H HN H N prenyl SAM N-methyl oxidoreductase/ 2 transferase transferase catalase Me CO2H CO2H HN HN Me OPP H2N Me NH

OH O Me

Me Me H EasD H EasG H ? NHMe NHMe NMe + p450 H NAD H NADPH H oxidase reductase monooxygenase

HN HN HN chanoclavine-I chanoclavine-I aldehyde agroclavine

O OH OH HO O

cloA H H ? NMe NMe NMe p450 oxidase isomerase H H H

HN HN HN lysergic acid elymoclavine paspalic acid Jakubczyk, D.; Cheng, J. Z.; O’Connor, S. E. Nat. Prod. Rep. 2014, 31, 1328. Chemistry and Biology of Hallucinogens lysergic acid diethylamide

O NEt2 Sandoz Laboratories, Basel, Switzerland first synthesized from lysergic acid November 16, 1938, searching for novel analeptics NMe 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. Chemistry and Biology of Hallucinogens lysergic acid diethylamide

O NEt2 Sandoz Laboratories, Basel, Switzerland first synthesized from lysergic acid November 16, 1938, searching for novel analeptics NMe H accidentally ingested April 16, 1943 intentionally ingested 250 μg April 19, 1943, HN known as “Bicycle Day” 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 Sandoz Laboratories, Basel, Switzerland first synthesized from lysergic acid November 16, 1938, searching for novel analeptics NMe H accidentally ingested April 16, 1943 intentionally ingested 250 μg April 19, 1943, HN known as “Bicycle Day” 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. 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. Chemistry and Biology of Hallucinogens lysergic acid diethylamide

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. Chemistry and Biology of Hallucinogens lysergic acid diethylamide

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 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

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 X-Ray crystal structure of 5-HT2B bound to LSD revealed key L209 residue acting as “lid” HN simulations show L229 serves same role for 5-HT2A LSD

exceptionally slow dissociation t½ > 220 minutes at 3 body temperature (37 ºC) in 5-HT2A in [ H] studies

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 X-Ray crystal structure of 5-HT2B bound to LSD revealed key L209 residue acting as “lid” HN simulations show L229 serves same role for 5-HT2A LSD

exceptionally slow dissociation t½ > 220 minutes at 3 body temperature (37 ºC) in 5-HT2A in [ H] studies

CO H CO H 2 2 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 NHMe NMe NMe 1. H2SO4 1. SOCl2 1. Ac2O H H H H 2. KOH; Raney Ni 2. NaCN, HCN 2. NaBH4; Na3AsO4•H2O 54% yield HCl AcN AcN HN HN 16% yield 57% 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. Chemistry and Biology of Hallucinogens 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 R NH2 NH2 N

CO2H

RO N N N H H H tryptophan tryptamine hallucinogen Chemistry and Biology of Hallucinogens psilocybin

Me O H N Me 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. Chemistry and Biology of Hallucinogens psilocybin

OH Me HO OH Me Me O H N Me N Me 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. Chemistry and Biology of Hallucinogens tryptamine pharmacokinetics

Me Me N NH2

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. Chemistry and Biology of Hallucinogens tryptamine pharmacokinetics

Me Me N NH2

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. Chemistry and Biology of Hallucinogens tryptamine pharmacokinetics

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. Chemistry and Biology of Hallucinogens 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)

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 Chemistry and Biology of Hallucinogens 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 CO H HO NH MeO NH 2 decarboxylase 2 COMT 2

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. Chemistry and Biology of Hallucinogens mescaline pharmacokinetics

[14C]mescaline in humans

RO NH2 MeO NH2 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. Chemistry and Biology of Hallucinogens 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. Chemistry and Biology of Hallucinogens 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. Chemistry and Biology of Hallucinogens synthetic phenethylamines

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

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. Chemistry and Biology of Hallucinogens synthetic phenethylamines

NH2 MeO NH 2 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. Chemistry and Biology of Hallucinogens synthetic phenethylamines

NH2 MeO NH 2 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

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 Me Me O O 2. NH3 O O 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. Chemistry and Biology of Hallucinogens MDMA metabolism and pharmacokinetics

HO NH O NHMe CYP3A4 O NH2 CYP2D6 2

Me Me Me O N-demethylation O demethylenation HO MDMA MDA HHA 24% 2% <1% COMT CYP2D6 t ~ 2h, t ~ 8-9 h demethylenation max ½ SAM methyl transferase

HO NHMe MeO NHMe MeO NH COMT CYP?? 2 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. Chemistry and Biology of Hallucinogens 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. Chemistry and Biology of Hallucinogens 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 Physiological processes: agonist, mimicking glutamate synaptic plasticity (learning, memory) Ca2+, Na+ into cell, K+ out of cell

Clinical importance:

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. Chemistry and Biology of Hallucinogens 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. Chemistry and Biology of Hallucinogens ketamine pharmacology

Me Me O O O HN HN NH CYP2B6 2

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. Chemistry and Biology of Hallucinogens ketamine pharmacology

Me Me O O O HN HN NH CYP2B6 2

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. Chemistry and Biology of Hallucinogens 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. Chemistry and Biology of Hallucinogens 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 drugs. They have a true N OMe N OMe 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

Morris, H.; Wallach, J. Drug Test. Analysis 2014, 6, 614. 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 Chemistry and Biology of Hallucinogens 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

Location:

cell membrane of nerve cells, in HN NH2 HN NH2

brain and spinal cord NH NH H2N

O O O H H H O N N N N N N N Endogenous ligand: H H H O OH O O O NH H NH Me O N N H O O NH O dynorphins HN O H2N HN NH2

H2N Physiological processes: dynorphin A pain OH consciousness

addiction HO Clinical importance: MeO targeted for analgesic effects OH O N Et potentially a natural addiction O N control mechanism H 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. Chemistry and Biology of Hallucinogens 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 O Ki = 2.4 nM, EC50 = 1.8 nM 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. Chemistry and Biology of Hallucinogens 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 O O BOMO O O O TBAF H Me O BOMO H H O AcO 99% Me O O Me OH Me MeO OMe 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. Chemistry and Biology of Hallucinogens

CB1 receptor

H2N 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 appetite O Me OH Clinical importance: 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. Chemistry and Biology of Hallucinogens

CB1 receptor

Location:

nerve cell membrane receptors, primarily in brain and spinal cord

Endogenous ligands:

arachidonic acid derivatives

Physiological processes:

pain, mood, memory appetite

Clinical importance:

substance abuse obesity

Shao, Z.; Yin, J.; Chapman, K.; Grzemska, M.; Clark, L.; Wang, J.; Rosenbaum, D. M. Nature 2016, 540, 602. Janero, D. R.; Makriyannis, A. Exp. Op. Emerg. Drugs 2009, 14, 43. Pertwee, R. G. et al. Pharmacol. Rev. 2010, 62, 588. Chemistry and Biology of Hallucinogens

CB1 receptor

Location:

nerve cell membrane receptors, primarily in brain and spinal cord

Endogenous ligands:

arachidonic acid derivatives

Physiological processes:

pain, mood, memory appetite

Clinical importance:

substance abuse obesity

HO Me CO2H

OH OH OH H CYP2C9 H H allylic oxidation H H 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. Chemistry and Biology of Hallucinogens tetrahydrocannabinol metabolism

HO Me CO2H

OH OH OH H CYP2C9 H H allylic oxidation H H 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. Chemistry and Biology of Hallucinogens synthetic cannabinoids

O O OH H

H N N Me O n-pent Me n-pent n-Bu THC JWH-018 JWH-073 Prof. John Huffman Ki (CB1) = 41 nM Ki (CB1) = 9 nM Ki (CB1) = 8.9 nM Clemson Ki (CB2) = 36 nM Ki (CB2) = 2.9 nM Ki (CB2) = 38 nM

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. Chemistry and Biology of Hallucinogens

“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 Chemistry and Biology of Hallucinogens