Transcript Effect of repeated administration of 18-MC

THE
NEUROSCIENCES
INSTITUTE
Albany Medical Center
Center for
Neuropharmacology
and Neuroscience
Ibogaine Analogues:
Drug Development for
Addictive Disorders
Stanley D. Glick, Ph.D., M.D.
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
Addicts are desperate
for new therapies
July 10, 1996
Dr. M.A. Geyer
Managing Editor
Psychopharmacology
Department of Psychiatry
School of Medicine
University of California San Diego
La Jolla, CA 92093-0804
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 Psychopharmacology.
1- 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 nicotineinduced 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,
IShofd
Isabelle Maisonneuvebbbbbbb
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,
Wtray
Isabelle Maisonneuve,
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 wasn’t the first time. I’ll try anything that might help me to stay clean
and straight. Please consider me as a candidate for your research protocol…”
VTA
February 16, 2009
“…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, I’ve
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 don’t 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…”
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.
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 55:303-310 (1993).
The search for a better ibogaine…
1. It had to be as effective as ibogaine.
2. It had to lack all the side effects of
ibogaine.
methyldesethylcoronaridine
desethylcoronaridine
18-benzyloxycoronaridine
ibogaine
albifloranine
18-methoxycoronaridine
acetate
ibogamine
coronaridine
tabernanthine
noribogaine
nortabernanthine
CHOH
O
3H
CC
C
H
OCH
H
CH
2H
43OCH
2Ph
22H
4
54OAc
3
CH
H
OH
3O
COH2CH3
Is 18-MC a potential treatment
for drug dependence?
1. Is 18-MC effective in reducing
drug self-administration?
2. Is 18-MC effective in reducing
signs of drug withdrawal?
Drug self-administration
Effect of an ideal treatment
number of responses
The ideal treatment
will not affect
responding for a nondrug reinforcer (e.g.,
water, food, sucrose).
The ideal treatment
will depress responding
for a drug of abuse
Treatment dosage
Effects of 18-MC on responding
for morphine, cocaine and water
18-MC selectively
decreases morphine
and cocaine selfadministration.
120
*
80
Ibogaine also affects
responding for water.
*
60
120
*
Water
40
20
0
Cocaine
100
*
Morphine
0
10
20
30
18-MC (mg/kg, i.p.)
*
*
40
Percent of baseline
Percent of baseline
100
80
60
40
Water
Cocaine
Morphine
20
0
0
10
20
30
Ibogaine (mg/kg, i.p.)
40
Effects of 18-MC on responding
for methamphetamine and nicotine
120
Female rats
Percent of baseline
100
80
60
*
40
*
*
*
20
*
*
Methamphetamine
0
Nicotine
0
*
10
20
30
18-MC (mg/kg, i.p.)
*
40
18-MC selectively
decreases
methamphetamine and
nicotine selfadministration, but is
most potent in
decreasing nicotine
self-administration.
Effects of 18-MC on alcohol intake
50
100
Food intake (g/kg/day)
75
30
*
*
*
20
25
10
0
50
Food intake
0
Alcohol intake
10
20
30
18-MC (mg/kg, i.p.)
40
Alcohol intake (ml/kg/day)
40
18-MC decreases
alcohol intake at
doses that do not
affect food intake.
0
Rezvani et al., Pharmacol. Biochem.
Behav., 58:615-619 (1997).
18-MC reduces
the efficacy of morphine
18-MC produces a
significant downward
shift in the doseresponse curve for
morphine selfadministration.
Infusions/hour
30
20
10
Vehicle
0
0.00
18-MC (40 mg/kg, p.o.)
0.04
0.08
0.12
0.16
Morphine (mg/kg/infusion)
I don’t like
morphine as
much since I
took 18-MC
Opioid withdrawal
morphine
7 days
naltrexone
•weight loss
•wet dog shakes
•flinching
•teeth chattering
•grooming
•burying
•diarrhea
Effects of 18-MC
on opioid withdrawal signs
3
*
10
5
0
10
20
18-MC (mg/kg, i.p.)
Control
10
20
18-MC (mg/kg, i.p.)
40
Grooming
Grooming
60
*
40
20
*
1
0
Control
10
20
18-MC (mg/kg, i.p.)
40
Control
10
20
15
10
5
0
40
Control
10
20
18-MC (mg/kg, i.p.)
40
30
*
20
10
0
2
20
18-MC (mg/kg, i.p.)
Teeth
chattering
Teeth chattering
5
0
40
80
0
10
Control
10
20
18-MC (mg/kg, i.p.)
*
40
Burying
Burying
Wet dog
shakes
Wet dog shakes
100
Control
Diarhea
Diarrhea
15
Flinching
Flinching
Weight
loss
Weight loss
15
10
5
0
Control
10
20
18-MC (mg/kg, i.p.)
*
40
18-MC reduces
the intensity of
several signs of
morphine
withdrawal
18-MC is a potentially effective
anti-addictive treatment
1. 18-MC decreases the selfadministration of multiple drugs
of abuse.
2. 18-MC alleviates several signs of
morphine withdrawal.
Does 18-MC have side effects?
1. Nerve cell damage?
2. Cardiovascular toxicity?
3. Is 18-MC likely to cause hallucinations?
4. Is 18-MC addictive (i.e., reinforcing)?
18-MC has no cerebellar toxicity
Ibogaine
18-MC
One month after
3x100mg/kg, i.p.
Ibogaine at very
high doses
damages
Purkinje cells.
18-MC at very
high doses does
not produce any
Purkinje cell
damage.
Percent of baseline
Effects of 18-MC and ibogaine
on heart rate and blood pressure
Systolic
125
Diastolic
Heart rate
100
75
18-MC
vehicle
0
20
40
60
80
100
120
140
160
18-MC (200
mg/kg, ip) has
no apparent
effects on
heart rate and
blood pressure.
180 200 220 240
Percent of baseline
Time (minutes)
Systolic
125
Diastolic
Heart rate
Ibogaine (200
mg/kg, ip)
decreases heart
rate without
altering blood
pressure.
100
75
vehicle
0
20
ibogaine
40
60
80
100
120
140
Time (minutes)
160
180 200 220 240
18-MC does not increase
extracellular serotonin levels
3000
Ibogaine
Percent of Baseline
2500
*
18-MC
(40 mg/kg, i.p.)
**
2000
*
1500
*
1000
Ibogaine, but not
18-MC, increases
extracellular
serotonin levels in
the nucleus
accumbens.
*
*
*
500
0
-60
0
60
Time (minutes)
120
180
So I won’t
hallucinate?
Cumulative responses
cocaine
saline
18-MC
40
saline
30
20
10
0
0
10
20
30
40
Time (min)
50
60
Cumulative
responses
Cumulativeresponses
responses
Cumulative
Cumulative responses
18-MC itself is not reinforcing
40
40
cocaine (0.4 mg/kg/infusion)
30
20
10
0
0
10
20
30
40
Time (min)
50
60
cocaine
(0.4mg/kg/infusion)
mg/kg/infusion)
saline
18-MC (0.8
30
20
10
0
0
10
20
30
40
Time (min)
50
60
18-MC has no apparent
side effects
1. Unlike ibogaine, 18-MC does not induce
tremors and does not damage the
cerebellum.
2. Unlike ibogaine, 18-MC has no ill effect
on the heart.
3. 18-MC may not be hallucinogenic.
4. 18-MC is not reinforcing and should not
be liable to abuse.
What is the mechanism
of action of 18-MC?
PFC
NAC
18-MC may interact with
the “reward pathways”.
VTA
PFC = prefrontal cortex
NAC = nucleus accumbens
VTA = ventral tegmental area
dopaminergic
neurons
In vivo
microdialysis
Effect of 18-MC on sensitized
cocaine-induced dopamine release
2500
2500
Percent of baseleine
Acute
Chronic cocaine:
2000
2000
Vehiclepretreated
18-MC1500
1500
pretreated
1000
1000
After chronic
administration cocaine
Acute
cocainethe
18-MC
abolishes
releases
much more
increases
dopamine
sensitization
of
dopamine in the
release
in the nucleus
cocaine-induced
nucleus
accumbens.
accumbens.
dopamine
This is release.
called
sensitization.
Cocaine
(20 mg/kg, i.p.)
500
500
0
-60
0
60
60
Time (min)
(min)
120
120
150
150
18-MC abolishes drug sensitization.
Why is this important?
relapse
craving
abstinence
use
abuse
addiction
Drug sensitization may underlie craving and
the cyclic nature of addiction.
By abolishing drug sensitization 18-MC may
prevent relapse and promote abstinence.
Ibogaine and 18-MC binding affinities
(Ki in mM)
Ibogaine
Kappa opioid
Mu opioid
Delta opioid
Nociceptin
NMDA
D1
D2
D3
M1
M2
5-HT1A
5-HT1B
5-HT1C
5-HT1D
5-HT2A
5-HT2C
5-HT3
Sodium channel
Sigma 1
Sigma 2
GABA B
NE uptake
5-HT uptake
18-MC
2.2 ± 0.10 5.1 ± 0.50
2.0 ± 0.15 1.1 ± 0.30
>10 3.5 ± 0.05
>100
>100
3.1 ± 0.30
>100
>10
>100
>10
16 ± 0.60
70 ± 1.7
25 ± 2.5
16 ± 1.0
32 ± 3
31 ± 3.4
>100
>100
46 ± 4.9
>100
>100
>100
>100
>100
>10
16
40 ± 3.4
>10
>100
2.6 ± 0.23 3.8 ± 0.067
3.6 ± 0.35 6.4 ± 0.68
2.5 ± 0.6
>100
0.4 ± 0.036
13 ± 1.2
>100
>100
>100
>10
4.1 ± 0.83
>10
With which
receptors
does 18-MC
interact?
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.
Effect of 18-MC
on nicotine-induced dopamine release
350
Vehicle
18-MC, administered 19
hours beforehand,
abolishes nicotine-induced
dopamine release in the
nucleus accumbens.
18-MC (40 mg/kg, i.p.)
Percent of Baseline
300
250
200
So 18-MC may
block nicotinic
receptors. But
which ones?
*
*
*
150
100
50
Nicotine (80 mg, i.v., 5 min)
-30
0
30
Time (minutes)
60
Patch-clamp electrophysiology
Whole-cell recording
In the presence of receptor agonist
Recording
system
Patch-pipette
Cell
Receptor
Movement of positive ions from the
outside to the inside of the cell is an
INWARD current and is shown as a
DOWNWARD deflection.
This is due to
receptor
desensitization.
18-MC interacts with
34 nicotinic receptors
1 sec
Ach 1 mM
18-MC 20 mM
IBO 20 mM
200 pA
200 pA
200 pA
1 sec
1 sec
18-MC and ibogaine
block the nAch
receptor currents
in cells cotransfected with
rat 3 and 4
receptor subunits.
18-MC does not interact with
42 nicotinic receptors
50% inhibition
Ach 300 mM
18-MC 5 mM
IBO 5 mM
10 sec
250 pA
250 pA
10 sec
Ibogaine, but not
18-MC, blocks the
nAch receptor
currents in cells
co-transfected
with rat 4 and 2
receptor subunits.
Where are 34 nicotinic
receptors located ?
medial habenula
interpeduncular nucleus
Connections between habenulointerpeduncular and mesolimbic systems
mHb
NAC
IP
VTA
PFC
NAC
mHb
MD
VTA
IP
NAC
mHb
R
VTA
IP
mHb = medial habenula
IP = interpeduncular nucleus
VTA = ventral tegmental area
NAC = nucleus accumbens
R = raphe nuclei
PFC = prefrontal cortex
MD = medial dorsal thalamic nucleus
Is 18-MC blockade of 34 nicotinic
receptors relevant to
its anti-addictive effects?
1. Effects of combination of low doses of nonspecific 34 nicotinic receptors on drug selfadministration
2. Effects of interpeduncular and intrahabenular
infusion of 18-MC on drug self-administration
3. Correlations between potencies of 18-MC
congeners to block 34 nicotinic receptors
and their effects on drug self-administration
Non-specific 34 nicotinic antagonists
DRUG
IC50 (mM)
mecamylamine
bupropion
dextromethorphan
0.09-1.0 (Papke et al., 2001; Hernandez et al., 2000)
1.4 (Fryer and Lukas, 1999)
8.9 (Hernandez et al., 2000)
18-MC
0.75
(Glick et al., 2002)
Mecamylamine, an antihypertensive agent (Inversine®), is a nonspecific 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.
Effects of 34 drug combinations
on morphine self-administration
45
40
Baseline
Treatment
Morphine Infusions/hour
35
30
*
25
*
*
20
15
*
10
*
*
5
0
Mec1 Bup5 DM5 MC1
Mec1 = mecamylamine (1 mg/kg, i.p.)
Bup5 = bupropion (5 mg/kg, i.p.)
Mec1 Mec1 Mec1 DM5 DM5 MC1
+
+
+
+
+
+
Bup5 DM5 MC1 Bup5 MC1 Bup5
DM5 = dextromethorphan (5 mg/kg, s.c.)
MC1 = 18-methoxycoronaridine (1 mg/kg, i.p.)
At low doses,
NONE of these
agents affected
morphine selfAll drug
administration.
combinations
REDUCED
morphine selfadministration.
Effects of 34 drug combinations
on methamphetamine self-administration
Methamphetamine Infusions/hour
35
30
Baseline
Treatment
25
20
* * * * * *
15
All drug
combinations
REDUCED
methamphetamine
selfadministration.
10
5
0
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.)
Effects of 34 drug combinations
on nicotine self-administration
40
Nicotine Infusions/hour
35
Baseline
Treatment
30
25
*
20
15
* * * *
*
All drug
combinations
REDUCED
nicotine selfadministration.
10
5
0
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.)
Effects of 34 drug combinations
on water responding
1200
Baseline
Treatment
Water Bar Presses/hour
1000
NONE of the drug
combinations
had an effect on
responding for
water.
800
600
400
200
0
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.)
Effects of interpeduncular administration
of 18-MC on drug self-administration
Local administration of 18-MC (5-10 µg in 1 µl)
into both interpeduncular nuclei decreased
responding for morphine (and also
methamphetamine); similar results occurred
with the medial habenula.
Morphine Infusions/hour
30
25
IPN
IPN
VTA
20
*
15
*
*
*
10
5
0
0
10
18-MC (mg)
0
1
2
5
8
10 20
18-MC (mg)
0
10
Mecamylamine
(mg)
interpeduncular
nucleus
100
80
60
40
20
morphine
r = -.67
p < 0.05
85
90
95
100
Percent of 3 4 inhibition
Percent of baseline: self-administration
Percent of baseline: self-administration
Correlations between
blockade of 34 nicotinic receptors
and drug self-administration
100
80
How much a
congener of 18-MC
decreases drug
self-administration
is related to how
well it can block
34 nicotinic
receptors.
60
40
20
methamphetamine
r = -.75
p < 0.02
85
90
95
100
Percent of 3 4 inhibition
Is 18-MC blockade of 34 nicotinic
receptors relevant to
its anti-addictive effects?
1. Combinations of low doses of non-specific 34
nicotinic receptor antagonists decrease drug
self-administration.
2. Interpeduncular or intrahabenular infusion of
18-MC decreases morphine self-administration.
3. There are significant correlations between
potencies of 18-MC congeners to block 34
nicotinic receptors and their effects on drug
self-administration.
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 ibogaine’s 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 34 nicotinic receptors
appears to be 18-MC’s most important action. 18-MC has
greater selectivity for this site than either ibogaine or
other existing agents.
Clinical application
Antagonism of acetylcholine’s actions at 34 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.
But… developing an anti-addictive medication is difficult.
…So we began the search for another clinical use of 18-MC.
Is 18-MC a potential treatment
for obesity?
Rationale:
• Consumption of sucrose and other sweet
substances is related to the
development of obesity.
• 18-MC (40 mg/kg) decreases the selfadministration of oral sucrose.
Percent of baseline
100
80
60
40
Water
Sucrose
20
0
0
10
20
18-MC (mg/kg)
30
40
Percent of baseline consumption
Effect of 18-MC
on consumption of sucrose
water
250
sucrose
18-MC decreases
sucrose intake but
not water intake
(*p<0.02-0.01).
200
150
100
50
0
0
10
*
*
*
20
18-MC (mg/kg)
40
Effect of 18-MC
on sucrose-induced weight gain
290
sucrose-vehicle (n=8)
sucrose-18MC (n=8)
Weight, g
280
270
260
250
240
0
***
** *
* ******
2
4
6
8
10 12
Days
14
*
****
16
18
*
20
*
18-MC (20 mg/kg for
14 days) blocks the
development of
sucrose-induced
obesity (*p<0.05-0.001).
22
Effect of repeated administration of 18-MC (20 mg/kg
i.p. for 14 days) on body fat depots. On the eighth day after
the last injection of 18-MC, animals were euthanized, and necropsies were
performed to remove periovarian, perirenal and inguinal fat pads.
20
Fat depot weight, g
15
*
10
5
0
Vehicle
18-MC
Conclusion
18-MC is potentially useful in the treatment
of obesity.
Follow-up (recent data)
18-MC also blocks the development of obesity induced by a
high fat diet.
18-MC reduces ghrelin-induced sucrose intake.
18-MC’s anti-obesity effects are centrally mediated (e.g.,
intraventricular 18-MC decreases fat depots).
• New start-up company focused on development of
18-MC and related treatments for drug addiction
• 18-MC to be synthesized and supplied by Obiter
Research (medicinal chemistry company)
• Combinations of generic drugs to be tested first
(rationale based on 18-MC’s mechanism of action)
COLLABORATORS
Isabelle Maisonneuve
Martin Kuehne
PFC
Lindsay Hough Helen Molinari
VTA
Milt Teitler Katharine Herrick-Davis
Mark Fleck
Christopher Pace
NAC
Karen Szumlinski Olga Taraschenko
Sarah McCallum