Ibogaine Analogues: Drug Development for Addictive Disorders

1
Ibogaine Analogues Drug Development for
Addictive Disorders
Center for Neuropharmacology and Neuroscience
Albany Medical Center
Stanley D. Glick, Ph.D., M.D.
2
Drug Abuse / Drug Dependence

• Drug/substance abuse
• Self-administered use of any drug/substance in a
  manner that deviates from the approved medical or
  social standards within a given culture
• Addiction or psychological dependence
• Repeated, compulsive seeking or use of a
  substance despite adverse social, psychological
  and/ or physical consequences
• Chronic relapsing disorder
• Physical dependence
• Adaptive, physiological state produced by
  repeated drug administration that is manifested
  as a withdrawal syndrome.

ADDICTION can occur without PHYSICAL
DEPENDENCE PHYSICAL DEPENDENCE can occur without
ADDICTION
3
Addicts are desperate for new therapies
December 9, 1999 I am currently married and
have a three year old daughter. I have used
heroin on and off since I was 16 years old, more
on than off I have attended numerous substances
abuse program and detoxes I started a business
and bought a house with my wife. Unfortunately,
I am losing both due to my addiction. I crave
heroin constantly, only heroin. I overdosed ten
days ago and this wasnt the first time. Ill
try anything that might help me to stay clean and
straight. Please consider me as a candidate for
your research protocol February 16, 2000 I
am 63 years old and I have been using heroin for
well over 25 years, never having the willpower or
success to kick the habit once and for all. At
this point I know that I must stop and
desperately want to. Somehow, Ive managed to
hold onto my county job for the past 13 years,
and must continue to keep it for at least 4 more
years. We have recently filed for bankruptcy,
and our condo is in foreclosure yet it can
become even worse if I dont get a grip on this
habit. I have many reasons to stop, not least of
all for the sake of my children, grandchildren
and wife who is not at all that well herself. I
would be so very grateful sir, if you could take
the time to give me some idea, some direction as
to how I might go about signing up or at least
trying to participate in your research
IShofd
VTA
July 10, 1996 Dr. M.A. Geyer Managing
Editdggggggggor Psychopharmacology University of
California Sa Dear Dr. Geyer
Enclosed are four copies of our revised
manuscript (MS96MG-095) entitled, "Ibogaine And
The Dopaminergic Response To Nicotine,"
authored by S.D. Glick, G.L. Mann, C.R. Deibel
and myself which we would like to resubmit for
publication in Psychopharmacolog1- We do not
think that it would be appropriate to discuss the
report of Dworkin et al. (1995) in this
manuscript, since we do not report any
self-administration results. Dworkin, using
Fisher rats, reported that ibogaine alters all
reinforcers (food, drug) with limited effects a
day later. Our laboratory, using Sprague Dawley
rats, showed that ibogaine alters all reinforcers
(water, drug) on the day of its administration,
but only the drug reinforcers later on (Glick et
al. 1991). The strain difference may explain this
inconsistency. It should also be noted that
Cappendijk and Dzoljic (1993) reported effects of
ibogaine on cocaine self-administration that were
very similar to our results (Glick et al. 1994).
The effects of mecamylamine on DOPAC and HVA
increases induced by nicotine are described in
the results section and, as requested by the
reviewer, plotted as Figure 3. We have
incorporated in Figure 2 the dopamine baseline
values preceding mecamylamine administration and
the 30 min levels prior to nicotine infusion. In
the discussion (pages 12-13) the effects of
ibogaine and mecamylamine on the dopamine
response to nicotine are compared, and the
greater efficacy of ibogaine to alter the
nicotine-induced increase in dopamine as compared
to DOPAC and HVA is addressed. It is true that
the phenomenon of nicotine-induced
desensitization has been widely studied using
numerous techniques. However, direct in vivo
neurochemical measurements were made only by
Damsma in 1989 who did not observe any acute
tolerance to the dopaminergic response to
nicotine. In this context, our findings are very
interesting. Thank you for your
consideration.


Sincerely,


Isabelle Maisonneuve,
Wtray
4
Once upon a time in Africa
Tabernanthe iboga shrub
Cameroon Eq. Guinea Gabon 2 Congos
Ibogaine is contained in the roots of the shrubs.
Ibogaine has been used for centuries in rituals
of the Bwiti religion.
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(No Transcript)
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At very high concentrations, side effects are
present
Degeneration of Purkinje cells in parasagittal
zones of the cerebellar vermis after treatment
with ibogaine or harmaline. O'Hearn, E. and
Molliver, M.E. Neuroscience 55303-310 (1993).
7
The search for a better ibogaine

• It had to be as effective as ibogaine.
• It had to lack all the side effects of ibogaine.

8
Is 18-MC a potential treatmentfor drug
dependence?

• Is 18-MC effective in reducingdrug
  self-administration?
• Is 18-MC effective in reducing signs of drug
  withdrawal?

9
Drug self-administration
10
Effect of an ideal treatment
The ideal treatment will not affect responding
for a non-drug reinforcer (e.g., water, food,
sucrose).
The ideal treatment will depress responding for
a drug of abuse
number of responses
Treatment dosage
11
Effects of 18-MC on respondingfor morphine,
cocaine and water
18-MC selectively decreases morphine and cocaine
self-administration.

Ibogaine also affects responding for water.





12
Effects of 18-MC on respondingfor
methamphetamine and nicotine
18-MC selectively decreases methamphetamine and
nicotine self-administration, but is most potent
in decreasing nicotine self-administration.
Female rats








13
Effects of 18-MC on alcohol intake
18-MC decreases alcohol intake at doses that do
not affect food intake.



Rezvani et al., Pharmacol. Biochem. Behav.,
58615-619 (1997).
14
18-MC reduces the efficacy of morphine
18-MC produces a significant downward shift in
the dose-response curve for morphine
self-administration.
I dont like morphine as much since I took 18-MC
15
18-MCs effects on drug self-administration are
persistent
18-MC decreases morphine self-administration for
48 hours
18-MC decreases cocaine self-administration for
24 hours
16
Opioid withdrawal

• weight loss
• wet dog shakes
• flinching
• teeth chattering
• grooming
• burying
• diarrhea

17
Effects of 18-MCon opioid withdrawal signs
Weight loss


Diarhea
Wet dog shakes
Grooming

18-MC reduces the intensity of several signs of
morphine withdrawal

Teeth chattering
Burying


18
18-MC is a potentially effective anti-addictive
treatment

• 18-MC decreases the self-administration of
  multiple drugs of abuse.
• 18-MC alleviates several signs of morphine
  withdrawal.

19
Does 18-MC have side effects?

• Nerve cell damage?
• Cardiovascular toxicity?
• Is 18-MC likely to cause hallucinations?
• Is 18-MC addictive (i.e., reinforcing)?

20
18-MC has no cerebellar toxicity
18-MC at very high doses does not produce any
Purkinje cell damage.
Ibogaine at very high doses damages Purkinje
cells.
21
Effects of 18-MC and ibogaineon heart rate and
blood pressure
18-MC (200 mg/kg, ip) has no apparent effects on
heart rate and blood pressure.
Ibogaine (200 mg/kg, ip) decreases heart rate
without altering blood pressure.
22
18-MC does not increaseextracellular serotonin
levels
Ibogaine, but not 18-MC, increases extracellular
serotonin levels in the nucleus accumbens.








So I wont hallucinate?
23
18-MC itself is not reinforcing
cocaine
saline
18-MC
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18-MC has no apparentside effects

• Unlike ibogaine, 18-MC does not induce tremors
  and does not damage the cerebellum.
• Unlike ibogaine, 18-MC has no ill effect on the
  heart.
• 18-MC may not be hallucinogenic.
• 18-MC is not reinforcing and should not be liable
  to abuse.

25
What are the pharmacokinetic properties of 18-MC?

• What is its half-life?
• Is it uniformly distributed throughout the body?
• Does it have any metabolites?

26
Pharmacokinetics of 18-MC (40 mg/kg, i.v.)
The data do not fit a one-compartment model.
27
Tissue distribution of 18-MC(4 hr)
18-MC is sequestered in fat.
28
18-MC metabolites(TLC)
18-MC may have several metabolites the most
important one has been shown to be
18-OH-coronaridine.
29
What is the mechanism of action of 18-MC?
18-MC may interact with the reward pathways.
PFC prefrontal cortex NAC nucleus
accumbens VTA ventral tegmental area
dopaminergic neurons
30
In vivo microdialysis
31
Effect of 18-MC on sensitized cocaine-induced
dopamine release
After chronic administration cocaine releases
much more dopamine in the nucleus accumbens.
This is called sensitization.
Acute cocaine increases dopamine release in the
nucleus accumbens.
18-MC abolishes the sensitization of
cocaine-induced dopamine release.
32
18-MC abolishes drug sensitization.Why is this
important?
Drug sensitization may underlie craving and the
cyclic nature of addiction. By abolishing drug
sensitization 18-MC may prevent relapse and
promote abstinence.
33
With which receptorsdoes 18-MC interact?
Ibogaine and 18-MC binding affinities(Ki in mM)
18-MC has no affinity for NMDA receptors.
18-MC has very low affinity for sigma receptors.
18-MC has no affinity for 5-HT uptake sites.
34
Effect of 18-MCon nicotine-induced dopamine
release
18-MC, administered 19 hours beforehand,
abolishes nicotine-induced dopamine release in
the nucleus accumbens.

So 18-MC may block nicotinic receptors. But
which ones?


35
Patch-clamp electrophysiologyWhole-cell recording
Recording system
Patch-pipette
Receptor
Cell
36
Whole-cell recording
In the presence of receptor agonist
This is due to receptor desensitization.
Movement of positive ions from the outside to the
inside of the cell is an INWARD current and is
shown as a DOWNWARD deflection.
37
18-MC interacts with ?3?4 nicotinic receptors
18-MC and ibogaine block the nAch receptor
currents in cells co-transfected with rat a3 and
b4 receptor subunits.
200 pA
200 pA
200 pA
1 sec
1 sec
1 sec
38
18-MC does not interact with ?4?2 nicotinic
receptors
Ibogaine, but not 18-MC, blocks the nAch receptor
currents in cells co-transfected with rat a4 and
b2 receptor subunits.
50 inhibition
250 pA
250 pA
10 sec
10 sec
39
Where are a3b4 nicotinic receptors located ?
40
Connections between habenulo-interpeduncular and
mesolimbic systems
R
mHb medial habenula IP interpeduncular
nucleus VTA ventral tegmental area NAC
nucleus accumbens R raphe nuclei PFC
prefrontal cortex MD medial dorsal thalamic
nucleus
MD
41
Is 18-MC blockade of a3b4 nicotinic receptors
relevant toits anti-addictive effects?

• Effects of combination of low doses of
  non-specific a3b4 nicotinic receptors on drug
  self-administration
• Effects of interpeduncular administration of
  18-MC on drug self-administration
• Correlations between potencies of 18-MC congeners
  to block a3b4 nicotinic receptors and their
  effects on drug self-administration

42
Non-specific ?3?4 nicotinic antagonists
DRUG IC50 (?M) mecamylamine 0.09-1.
0 (Papke et al., 2001 Hernandez et al., 2000)
bupropion 1.4 (Fryer and Lukas,
1999) dextromethorphan 8.9 (Hernandez et al.,
2000) 18-MC
0.75 (Glick et al., 2002)
Mecamylamine, an antihypertensive agent
(Inversine), is a non-specific nicotinic
receptor antagonist. Bupropion, an
antidepressant (Wellbutrin) and an anti-smoking
aid (Zyban), is also a dopamine uptake
blocker. Dextromethorphan, an antitussive in
many OTC cough medicines (Benylin, Delsym,
DexAlone, Pertussin, Robitussin, Sucrets), is
also a NMDA receptor antagonist.
43
Effects of ?3?4 drug combinationson morphine
self-administration
At low doses, NONE of these agents affected
morphine self-administration.
All drug combinations REDUCED morphine
self-administration.






Mec1 Bup5 DM5 MC1 Mec1 Mec1 Mec1
DM5 DM5 MC1

Bup5
DM5 MC1 Bup5 MC1 Bup5

• Mec1 mecamylamine (1 mg/kg, i.p.)
• Bup5 bupropion (5 mg/kg, i.p.)

DM5 dextromethorphan (5 mg/kg, s.c.) MC1
18-methoxycoronaridine (1 mg/kg, i.p.)
44
Effects of ?3?4 drug combinationson
methamphetamine self-administration
All drug combinations REDUCED methamphetamine
self-administration.






Mec1 Bup10 DM10 MC5 Mec1 Mec1 Mec1
DM10 DM5 MC5

Bup10
DM5 MC2 Bup10 MC2 Bup10

• Mec1 mecamylamine (1 mg/kg, i.p.)
• Bup10 bupropion (10 mg/kg, i.p.)
• DM5 dextromethorphan (5 mg/kg, s.c.)

DM10 dextromethorphan (10 mg/kg, s.c.) MC2
18-methoxycoronaridine (2 mg/kg, i.p.) MC5
18-methoxycoronaridine (5 mg/kg, i.p.)
45
Effects of ?3?4 drug combinationson nicotine
self-administration
All drug combinations REDUCED nicotine
self-administration.






Mec.1 Bup5 DM.5 MC.1 Mec.1 Mec.1
Mec.1 DM.5 DM.5 MC.1


Bup5 DM.5 MC.1 Bup5 MC.1 Bup5

• Mec.1 mecamylamine (0.1 mg/kg, i.p.)
• Bup5 bupropion (5 mg/kg, i.p.)

DM.5 dextromethorphan (0.5 mg/kg, s.c.) MC.1
18-methoxycoronaridine (0.1 mg/kg, i.p.)
46
Effects of ?3?4 drug combinationson water
responding
NONE of the drug combinations had an effect on
responding for water.
Mec1 Bup10 DM10 MC5 Mec1 Mec1 Mec1
DM10 DM5 MC5

Bup10
DM5 MC2 Bup10 MC2 Bup10

• Mec1 mecamylamine (1 mg/kg, i.p.)
• Bup10 bupropion (10 mg/kg, i.p.)
• DM5 dextromethorphan (5 mg/kg, s.c.)

DM10 dextromethorphan (10 mg/kg, s.c.) MC2
18-methoxycoronaridine (2 mg/kg, i.p.) MC5
18-methoxycoronaridine (5 mg/kg, i.p.)
47
Effects of interpeduncular administration of
18-MC on drug self-administration
interpeduncular nucleus

Local administration of 18-MC (10 µg in 1 µl)
into both interpeduncular nuclei, immediately
prior to the session, decreased responding for
morphine by 35.
48
Correlations between blockade of a3b4 nicotinic
receptorsand drug self-administration
How much a congener of 18-MC decreases drug
self-administration is related to how well it can
block a3b4 nicotinic receptors.
49
Is 18-MC blockade of a3b4 nicotinic receptors
relevant toits anti-addictive effects?

• Combinations of low doses of non-specific a3b4
  nicotinic receptor antagonists decrease drug
  self-administration.
• Interpeduncular administration of 18-MC decreases
  morphine self-administration.
• There are significant correlations between
  potencies of 18-MC congeners to block a3b4
  nicotinic receptors and their effects on drug
  self-administration.

50
Conclusions
1. 18-MC may be useful in treating many forms of
drug addiction, including opioid (e.g., heroin)
and stimulant (e.g., cocaine, methamphetamine)
abuse, alcoholism and smoking. 2. 18-MC should
lack all of ibogaines prominent side
effects. 3. 18-MC abolishes the dopamine
sensitization that occurs with chronic drug
administration and that may underlie craving and
relapse. 4. An antagonist action at a3b4
nicotinic receptors appears to be 18-MCs most
important action. 18-MC has greater selectivity
for this site than either ibogaine or other
existing agents.
51
Clinical application
Antagonism of acetylcholines actions at a3b4
nicotinic receptors may constitute a novel
mechanism and strategy for reducing addiction to
multiple drugs. Low dose combinations of
existing agents (i.e., dextromethorphan,
mecamylamine and bupropion) may be viable
therapies, and readily testable, in lieu of
single agents acting specifically at this site.
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COLLABORATORS Isabelle Maisonneuve Martin
Kuehne Lindsay Hough Milt Teitler Katharine
Herrick-Davis Helen Molinari Mark Fleck
PFC
VTA
NAC