Sustained decrease in cocaine-maintained responding in rhesus monkeys with 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-hydroxy-3- phenylpropyl)piperazinyl decanoate, a long-acting ester derivative of GBR 12909

Full text of DOI:10.1021/jm960551t

© Copyright 1996 by the American Chemical Society
Volume 39, Number 24
November 22, 1996
Communications to the Editor
extent that the desired effect of a potential medication
Su sta in ed Decr ea se in
would be a long-term decrement in drug-seeking be-
haviors, it was of interest to explore methods to extend
the duration of these effects. Previous studies have
shown that one method for producing a long-acting
agent is to esterify a polar hydroxyl-containing molecule
with a medium to long chain alkanoic acid, affording a
nonpolar oil-soluble molecule suitable for depot injection
(the high partition coefficient favors the oil phase,
resulting in the continuous release of a small proportion
of the compound into the plasma, until depleted).
Several successful depot preparations have been devel-
oped, with pharmacological half-lives of 30 days or
more.6,7 While assessing the abilities of a series of
different GBR 12909 analogs to inhibit DA reuptake and
decrease cocaine-maintained responding, some agents
were identified as suitable candidates for chemical
derivatization as decanoate esters. We chose 4 as the
most viable candidate for derivatization and depot
formulation based in part on its in vitro biological
activity (the measured values for binding to both the
dopamine transporter (DAT) and serotonin transporter
(SERT), along with its ability to inhibit the reuptake of
[3H]DA and [3H]-5HT, were essentially identical with
those for GBR 12909) and in part on behavioral data.
This report details some promising preliminary results
in the monkey.
Coca in e-Ma in ta in ed Resp on d in g in
Rh esu s Mon k eys w ith
1-[2-[Bis(4-flu or op h en yl)m eth oxy]eth yl]-
4-(3-h yd r oxy-3-p h en ylp r op yl)p ip er a zin yl
Deca n oa te, a Lon g-Actin g Ester
Der iva tive of GBR 12909
J ohn R. Glowa,*,†,‡ William E. Fantegrossi,†,‡
David B. Lewis,‡ Dorota Matecka,‡
Kenner C. Rice,‡ and Richard B. Rothman§
Department of Psychiatry, Uniformed Services University
of the Health Sciences, Bethesda, Maryland 20814,
Laboratory of Medicinal Chemistry, NIDDK, NIH,
Bethesda, Maryland 20892-5550, and
Clinical Psychopharmacology Section, NIDA,
Baltimore, Maryland 22041
Received J uly 29, 1996
Cocaine abuse continues to be a serious public health
problem, for which effective treatments are sought.
Since a hallmark feature of abused drugs is their ability
to support self-administration (drug-seeking) behavior
in animals,1 preclinical evaluations of potential phar-
macotherapies for treatment of cocaine abuse have
focused on this behavior. Recent studies have shown
that the high-affinity dopamine (DA) reuptake inhibitor
GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-
(3-phenylpropyl)piperazine)2 can selectively decrease
cocaine self-administration, without affecting compa-
rable performances maintained by food, in rhesus mon-
keys.3 Subsequent studies4 showed that repeated treat-
ments with lower doses could sustain these behaviorally
selective effects. Together with the observation that
GBR 12909 attenuates cocaine-induced activation of
mesolimbic dopamine neurons, as measured by in vivo
microdialysis,5 these data suggest that DA reuptake
inhibitors may be useful pharmacological adjuncts in
the treatment of cocaine abuse in humans. To the
Seven adult, male rhesus monkeys, weighing between
7.5 and 9.0 kg, served as subjects. Each had been
previously trained under various schedules of food and
cocaine self-administration.3,4 Food (three 1 g banana
pellets) was delivered by a dispenser in front of the
monkey. Cocaine was delivered through the momentary
activation of a syringe driver connecting the drug supply
to a subcutaneous vascular access port.8 Responding
was maintained under a multiple fixed ratio (FR) 30-
response food, FR30 cocaine (10 µg/kg/inf), time-out (TO)
10-min schedule.3,4 Availability of food or cocaine
alternated during brief periods of a 2-h session. In each
period, a maximum of 10 reinforcer deliveries could be
produced. Availability of each reinforcer was con-
strained by a 60-s limited hold. Periods of food and drug
availability were separated by a 10-min TO, and ses-
sions always began with a food component. Once
responding was stable ((20% over at least 8-10 con-
* Address for correspondence: Dept. of Pharmacology and Thera-
peutics, LSUMC - S, 1501 Kings Highway, P.O. Box 33932, Shreveport,
LA 71130-3932. Tel: 318-675-4803. Fax: 318-675-7857.
† Uniformed Services University of the Health Sciences.
‡ NIDDK.
§ NIDA.
S0022-2623(96)00551-1
This article not subject to U.S. Copyright. Published 1996 by the American Chemical Society

4690 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Communications to the Editor
Sch em e 1a
a
(a) Acetone, 25 °C; (b) LAH, THF, 25 °C; (c) n-C9H19COCl, CHCl3, 25 °C.
secutive sessions), monkeys were injected with 0, 1, 3,
or 6 mL of 5 solution9 and immediately run in a daily
experimental session. Two monkeys were studied per
dose, except for the 1-mL dose. Behavioral data were
collected as the session average rate of responding for
each component (food or cocaine) during individual daily
sessions and compared to control rates occurring before
treatment. Drug effects are described as the mean of
individual effects (percent of control rates for both food-
and cocaine-maintained responding) as a function of
dose of 5. Data for the first 24 days of treatment were
satistically analyzed by repeated measures ANOVA and
subsequently partitioned by two-factor repeated mea-
sures ANOVA.
Decanoate 5 was synthesized as shown in Scheme 1.
Monosubstituted piperazine 12a was substituted with
F igu r e 1. Mean effects of single injections of 5 (doses
expressed as total milliliters when given as a 50% (w/w)
solution in sesame oil) on rates of responding maintained by
food or cocaine in rhesus monkeys. Effects are expressed as
the mean percent of control rate, for food- or cocaine-
maintained responding, over the course of the 24-day treat-
ment period (n ) 2). *Effects at 6 mL were determined
significant by ANOVA.
3-chloropropiophenone (2) affording the ketone 32b-d in
88% yield after recrystallization as the bis-maleate salt,
mp 165-166 °C (MeOH). Ketone 3 underwent facile
reduction with lithium aluminum hydride, affording
racemic 4 in quantitative yield as the bis-HCl salt, mp
216-218 °C (i-PrOH). Benzylic alcohol 42b-d was then
treated with a 50% excess of decanoyl chloride in dry
ethanol-free chloroform, affording the decanoate ester
5, which was purified by formation of the bis-maleate
salt, mp 154-155 °C (MeOH), and conversion back to
the free base under mild, ammonia-free conditions (5%
aqueous NaHCO3). All new compounds gave NMR and
mass spectra consistent with their assigned structures
and gave C, H, N analyses within (0.4% of their
calculated values. Ester 5 was formulated for use by
adding an equal weight of sesame oil (Sigma) to its
ethereal solution, concentrating at reduced pressure,
and then evacuating at 0.1 Torr until constant mass was
reached. The formulated solution was calculated as
being a 49.9% (w/w) solution of 5 in sesame oil.
period with food- and cocaine-maintained responding
averaging 99.9% and 100.4% of control, respectively.
The lowest dose of 5 had no effect on food-maintained
responding (97% of control) and slightly decreased
(76.2% of control) cocaine-maintained responding, al-
though a downward trend in drug-maintained respond-
ing was clearer during the second and third week
following the injection and recovered to baseline levels
on subsequent days. An intermediate dose (3 mL) of 5
had a slight overall effect (82% of control) on food-
maintained responding and decreased cocaine-main-
tained responding to about 74% of control over the entire
treatment period. The were no differences in effect on
food- and cocaine-maintained responding at these lower
doses. In contrast, the highest dose of 5 tested (6 mL)
had no effect on food-maintained responding and de-
creased cocaine-maintained responding to 25.3% of
control over the entire treatment period. Figure 2
shows a small but observable effect of 5 on cocaine-
maintained responding during the first 5 days after the
injection. A robust statistical difference (F ) 55.919, p
) 0.017) in the effect of 5 on food- and cocaine-main-
tained responding occurred over the remaining treat-
Prior to treatment absolute control rates of respond-
ing (mean, coefficient of variation) were comparable for
food- (3.696 resp/s, (9.99%) and cocaine- (4.026 resp/s,
(13.6%) maintained responding. Three-factor ANOVA
determined a significant main effect of dose (F ) 11.031,
p ) 0.016), event (F ) 13.558, p ) 0.0059), and days of
treatment (F ) 7.905, p ) 0.0208). Figure 1 shows the
mean effect of treatment at each dose over the first 24
days immediately following a single injection. Nonin-
jection control values were stable over this treatment

Communications to the Editor
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4691
minimal blood levels of such preparations to decrease
drug-seeking behavior. This information should facili-
tate determination of minimum receptor occupancy for
decreases in drug-seeking behavior by noninvasive
methods such as PET or SPECT. Additional studies
should address issues related to whether the self-
administration dose-effect function changes in the
presence of 5. Some studies have suggested that in the
presence of acute doses of an agonist, the unit dose-
effect function for cocaine may shift to the left,11 while
others have only found evidence for a downward shift.3,12
The ability to maintain a relatively constant effect over
days would allow for a more effective means to assess
such possibilities. Finally, the well-established use of
long-acting decanoate formulations of antipsychotic
agents for treating poorly compliant patients suggests
that a decanoate formulation of a DA reuptake inhibi-
tor might also be useful for treating poorly compliant
cocaine-dependent patients. Positive results would
validate this preclinical approach to developing high-
affinity DA uptake inhibitors as medications for cocaine
dependence.13
F igu r e 2. Effects of the 6-mL dose of 5 on rates of responding
maintained by food or cocaine, for 28 sessions following a single
treatment in rhesus monkeys. Effects are expressed as the
mean percent of control rates for food- or cocaine-maintained
responding (n ) 2).
ment period, followed by a recovery in cocaine-main-
tained responding toward control levels approximately
30 days after the initial treatment.
Ack n ow led gm en t. These studies were supported
under NIDA RA-ND-94-24 and DA 09820 (J . R. Glowa,
The current results show that a single treatment with
a relatively selective DA reuptake inhibitor, formulated
to be long-acting, resulted in a sustained and selective
effect on cocaine-maintained responding for almost 30
days. These results are qualitatively and quantitatively
similar to those obtained with both acute3,4 and re-
peated4 daily administration of shorter-acting DA re-
uptake inhibitors, except only a single injection was
required. Thus, drug-seeking behavior can be sup-
pressed for periods assumed to be concordant with the
pharmacological half-life of the decanoate preparation.
These results are of particular interest because they
appear to be consistent with those expected of a long-
term medication for drug abuse, in that drug-seeking
was selectively decreased for a relatively long time. An
interesting observation of the current effects is that the
decanoate required several days to obtain full effect.
This observation is of interest because it suggests the
slow onset of similar agents may limit their abuse
potential. Previous studies have shown that by de-
creasing delivery rates of self-administered cocaine,
responding for drug declines. This decrement in the
reinforcing effects of cocaine, presumably mediated by
delayed reinforcement, is likely to be a desired effect of
formulating an slow-onset, long-acting, agonist-based
medication.
Although the hazards of performing pharmacological
studies on racemic compounds are well-known10 this
racemic compound displayed remarkable ability to
selectively decrease cocaine-seeking behavior in mon-
keys. This observation, combined with the potent in
vitro biological data for the parent hydroxy compound
4, suggests that our ongoing studies to determine the
relationship between chirality and the pharmacological
profile for 4 and related compounds will prove to be of
substantial interest. Of additional interest is the
pharmacological profile of compound 5 itself. Initial
experiments indicate that 5 potently inhibits DA bind-
ing, but these studies could not distinguish among
inhibition produced by 5, 4 formed by the action of
membrane-associated esterases in vitro, or their com-
bination. Further studies to dissociate these factors are
in progress. Yet other studies are planned to determine
PI).
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and binding data for compounds 3-5 (5 pages). Ordering
information can be found on any current masthead page.
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