Effects of substitution on the pyrrole N atom in derivatives of tetrahydronaltrindole, tetrahydrooxymorphindole, and a related 4,5-epoxyphenylpyrrolomorphinan

Article abstract of DOI:10.1021/jm040817t

The effect of substitution of the pyrrolo- and indolo-N atoms in tetrahydronaltrindole (TNTI), tetrahydrooxymorphindole (TOMI), and 17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-4′-phenyl-6,7:2′, 3′-pyrrolomorphinan (4) is reported. In opioid functional a

Full text of DOI:10.1021/jm040817t

J. Med. Chem. 2004, 47, 6645-6648
6645
Brief Articles
Effects of Substitution on the Pyrrole N Atom in Derivatives of
Tetrahydronaltrindole, Tetrahydrooxymorphindole, and a Related
4,5-Epoxyphenylpyrrolomorphinan
Sanjay K. Srivastava,† Shefali,† Carl N. Miller,‡ Mario D. Aceto,§ John R. Traynor,‡ John W. Lewis,† and
Stephen M. Husbands*,†
Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, U.K., Department of Pharmacology,
University of Michigan, Michigan 48109, and Department of Pharmacology and Toxicology,
Virginia Commonwealth University, Richmond, Virginia 23298
Received March 26, 2004
The effect of substitution of the pyrrolo- and indolo-N atoms in tetrahydronaltrindole (TNTI),
tetrahydrooxymorphindole (TOMI), and 17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-4′-
phenyl-6,7:2′,3′-pyrrolomorphinan (4) is reported. In opioid functional assays 4 were potent δ
opioid receptor (DOR) antagonists while the TNTI derivatives (7) were potent DOR antagonists
or low-efficacy DOR partial agonists without substantial selectivity. The TOMI derivatives (8)
were DOR agonists with significant selectivity. In vivo the DOR antagonist activity of 7d was
confirmed, but the predominant agonist effect of 8d was shown to be µ opioid receptor mediated.
Introduction
The 4,5-epoxyindolomorphinan structure (1) has been
the basis of many selective ligands for δ opioid receptors
(DOR) and κ opioid receptors (KOR).1-3 Extensive
investigations of SAR in 1 have particularly involved
substitution at N17 (R1), C14 (R2), C5 (R3), and the indole
aromatic ring (R4).1-10 Limited investigation of SAR for
substitution on the indolic N (R5) has been reported.7-10
N-Methylnaltrindole (2b) and N-phenylnaltrindole (2c)
had potent DOR antagonist activity in the mouse vas
deferens (mvd) assay but were 8- and 25-fold less potent
than naltrindole (NTI, 2a) and substantially less DOR-
selective.7 However, N-benzylnaltrindole (BNTI, 2d),
though slightly less potent as a DOR antagonist than
NTI, was of equivalent in vitro selectivity as a DOR
antagonist. Moreover, BNTI antagonized the selective
DOR agonist DSLET with very long duration after icv
administration in the mouse acetic acid induced ab-
dominal stretch assay (AS).9
We have recently used Michael addition chemistry on
Chemistry
The preparation of N-methyltetrahydronaltrindole
(7a) in 5% yield by Piloty synthesis from in situ
generated naltrexone-methylimine was previously re-
ported by Portoghese and co-workers.12 In the present
study 7a was prepared in 70% yield and the series in
57-82% yield by refluxing in ethanol in situ generated
oxymorphone imines (6) with 1-nitro-1-cyclohexene
(Scheme 1). By this method a variety of pyrrole-N
substituents could be introduced.
benzylimine derivatives of oxymorphones and oxyco-
dones with nitrostyrenes to source 4,5-epoxy-4′-arylpyr-
rolomorphinans with pyrrole N-benzyl substitution (e.g.,
4a, 5).11 Lead 4a was a selective antagonist in vitro and
in vivo versus DOR agonist induced nociception and
convulsions. The Michael addition between nitroolefins
and oxymorphone imines (6) has now been extended to
enable study in more detail of the effects of pyrrole N
substitution in 4,5-epoxypyrrolomorphinans, particu-
larly in derivatives of tetrahydronaltrindole (TNTI, 7)
and tetrahydrooxymorphindole (TOMI, 8).
Results
The new ligands were evaluated in binding assays in
human recombinant opioid receptors transfected into
Chinese hamster ovary (CHO) cells in which the dis-
placed radioligands were [3H]DAMGO (MOR, µ opioid
receptors), [3H]Cl-DPDPE (DOR), and [3H]U69593 (KOR)
(Table 1).13 The TNTI derivatives (7a-f) showed high
* To whom correspondence should be addressed. Phone: +44 (0)
1225 383103. Fax: +44 (0) 1225 386114. E-mail: s.m.husbands@
bath.ac.uk.
† University of Bath.
‡ University of Michigan.
§ Virginia Commonwealth University.
10.1021/jm040817t CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/16/2004

6646 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 26
Brief Articles
Table 2. [35S]GTPγS Binding in Cloned Human Opioid
Scheme 1a
Receptors
EC50/nM, % stim,a or (Ke/nM)b
R1
R
MOR
KOR
DOR
a (i) RNH2, TsOH, EtOH; (ii) 1-nitro-1-cyclohexene.
4a CH2cC3H5 C6H5CH2
4b CH2cC3H5 CH3
4c CH2cC3H5 CH3CH2
7a CH2cC3H5 CH3
7b CH2cC3H5 CH3CH2
7c CH2cC3H5 CH2cC3H5
7d CH2cC3H5 C6H5CH2
(8.09 ( 1.86)
(4.04 ( 0.49)
(10.7 ( 2.19)
(4.30 ( 0.35)
(5.32 ( 0.34)
(2.51 ( 0.13)
(8.13 ( 0.71)
(21.6 ( 1.71)
(34.1 ( 4.20)
(44.0 ( 4.72)
(12.2 ( 1.03)
14.3 ( 1.03, 63 3.25 ( 1.21, 25
(11.8 ( 1.15)
(49.8 ( 2.69)
(0.43 ( 0.09)
(0.62 ( 0.07)
(0.72 ( 0.08)
(0.47 ( 0.02)
Table 1. Binding Affinities to Cloned Human Opioid Receptors
Transfected into (CHO Cellsa
3.89 ( 1.31, 32
(2.23 ( 0.40)
7e CH2cC3H5 cC6H11CH2 (11.6 ( 0.70)
7f CH2cC3H5 C6H5(CH2)2 (5.66 ( 0.47)
54.3 ( 3.13, 84 68.2 ( 18.7, 37
13.8 ( 0.63, 76 110 ( 10.2, 36
8a CH3
CH3
222 ( 82.5, 39 97.2 ( 6.56, 69 8.52 ( 3.10, 68
175 ( 30.6, 41 98.2 ( 14.7, 66 10.3 ( 1.59, 76
732 ( 34.4, 44 1754 ( 228, 43 9.87 ( 1.48, 85
8b CH3
CH3CH2
C6H5CH2
8d CH3
8e CH3
8f CH3
cC6H11CH2 130 ( 8.10, 57 153 ( 1.10, 85 13.0 ( 3.23, 90
C6H5(CH2)2 175(14.3, 71 131 ( 1.24, 76 12.0 ( 2.15, 59
H (4.26 ( 0.3) (4.95 ( 0.32) (0.11 ( 0.005)
Ki ( SEM (nM)
2a CH2cC3H5
[3H]DAMGO [3H]U69593 [3H]Cl-DPDPE
a Percent maximal stimulation with respect to the standard
agonists DAMGO (MOR), U69593 (KOR), and DPDPE (DOR).
Mean of two experiments, each carried out in triplicate. b Values
are the mean of five or six experiments versus DAMGO (MOR),
U69593 (KOR), and DPDPE (DOR).
R1
R
(MOR)
(KOR)
(DOR)
4a
4b
4c
7a
7b
7c
7d
7e
7f
8a
8b
8d
8e
8f
CH2cC3H5 C6H5CH2
CH2cC3H5 CH3
CH2cC3H5 CH3CH2
CH2cC3H5 CH3
CH2cC3H5 CH3CH2
16.8 ( 6.18 120 ( 9.61 13.7 ( 0.30
7.60 ( 0.35 18.5 ( 1.97 3.35 ( 1.13
8.75 ( 0.37 24.3 ( 1.55 2.95 ( 0.63
5.76 ( 0.87 4.11 ( 0.28 2.01 ( 0.01
5.06 ( 0.38 7.38 ( 0.43 1.65 ( 0.29
CH2cC3H5 CH2cC3H5 2.52 ( 0.27 2.51 ( 0.50 1.81 ( 0.54
CH2cC3H5 C6H5CH2
5.39 ( 0.72 6.29 ( 0.17 2.94 ( 0.79
efficacy in the range 63-84% of the standard KOR
agonist U69593. The selectivity for DOR of the two all-
antagonist ligands (7a,d) was modest over MOR but
substantial over KOR and in both cases greater than
in the binding assays.
CH2cC3H5 cC6H11CH2 18.5 ( 5.15 24.9 ( 5.37 3.10 ( 1.12
CH2cC3H5 C6H5(CH2)2 7.46 ( 2.60 8.97 ( 0.47 1.80 ( 0.50
CH3
CH3
CH3
CH3
CH3
CH3
25.2 ( 3.07 89.1 ( 8.03 1.63 ( 0.60
25.8 ( 0.33 168 ( 12.0 2.67 ( 0.27
88.9 ( 33.5 289 ( 19.1 18.1 ( 4.19
CH3CH2
C6H5CH2
cC6H11CH2 17.9 ( 0.81 262 ( 7.79 4.17 ( 1.06
C6H5(CH2)2 15.4 ( 2.89 163 ( 22.9 5.00 ( 0.83
The DOR antagonist activity of the 1′(N)-benzyl
derivative (7d) was confirmed in vivo. In the phe-
nylquinone-induced abdominal stretch assay14 7d showed
significant antagonism of the selective DOR agonist
SNC80, but complete antagonism was not achieved. The
maximum antagonism achieved at 3 and 10 mg/kg 7d
sc was 54%. However, in this assay BNTI (2d) showed
a very similar DOR antagonist effect with maximum
antagonism of SNC80 (57%) at 1 mg/kg 2d sc. In
another in vivo test for DOR antagonist activity 7d (10
mg/kg sc) administered 20 min before SNC80 (32 mg/
kg) completely prevented SNC80-mediated convul-
sions.15
The 4,5-epoxypyrrolomorphinans (4a-c), which have
the 17(N)-cyclopropylmethyl group in common with the
TNTI derivatives (7), were antagonists for DOR, KOR,
and MOR in the [35S]GTPγS functional assays (Table
2). All three of these ligands had subnanomolar potency
as DOR antagonists, g50-fold higher than their potency
as KOR antagonists. DOR antagonist selectivity over
MOR was less impressive but similar to the DOR
selectivity of derivatives of TNTI (7). DOR antagonist
potency and overall selectivity of 4a-c was substan-
tially better than in the binding assays. The differences
between the individual 4,5-epoxypyrrolomorphinan de-
rivatives (4a-c) were insignificant and smaller than
between the equivalent derivatives of TNTI (7a,b,d).
2a, NTI CH2cC3H5
H
6.3 ( 2.3
10.1 ( 0.65 0.2 ( 0.05
a Data are the average from two experiments, each carried out
in triplicate.
affinity for DOR with Ki’s in the range 1.5-3.1 nM,
higher than the affinity for KOR and MOR but with low
levels of DOR selectivity. The equivalent derivatives of
TOMI (8a,b,d-f) displayed similar high affinity for
DOR with the exception of the N-benzyl derivative (8d)
that had lowest affinity for all three opioid receptor
types. Although limited, DOR-selectivity in the TOMI
series, particularly over KOR, was superior to that in
the TNTI series. In the 17(N)-cyclopropylmethyl-4,5-
epoxy-4′-phenylpyrrolomorphinan series the affinities
for DOR, KOR, and MOR of the 1′(N)-methyl and 1′-
(N)-ethyl derivatives (4b,c) were similar and higher
than those previously reported for the 1′(N)-benzyl
derivative (4a).11 The affinity for DOR of 4b and 4c was
higher than for KOR and MOR, but selectivity for DOR
was no more impressive than for 4a.
Opioid receptor functional activity was determined for
stimulation of [35S]GTPγS binding in recombinant hu-
man opioid receptors transfected into CHO cells.13 In
DOR assays 7a-f were potent antagonists (7a,d) or low-
efficacy agonists of varying potency (Table 2). The 1′-
(N)-ethyl (7b) and 1′(N)-cyclopropylmethyl (CPM; 7c)
derivatives had high potency DOR partial agonist
activity, but the cyclohexylmethyl and phenethyl ana-
logues (7e,f) were 20- to 30-fold less potent. All the TNTI
derivatives (7a-f) displayed MOR antagonist effects of
relatively high potency. The efficacy range for KOR
activity in this series was greater than for DOR or MOR
activity. In addition to 7a and 7d, which were antago-
nists for all opioid receptor types, 7c was also a KOR
antagonist. In contrast 7b,e,f had very substantial KOR
The derivatives of TOMI (8) in [35S]GTPγS assays
displayed DOR agonist activity of substantial efficacy
and potency (Table 2). Efficacy was 59-90% of the
efficacy of the standard selective DOR agonist DPDPE
with EC50 consistently close to 10 nM. KOR efficacy with
respect to the selective agonist U69593 was in the range
43% (1′-benzyl) to 85% (1′-cyclohexylmethyl), but KOR
potency was substantially lower than DOR potency,

Brief Articles
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 26 6647
typically by 1 order of magnitude and in the case of 8d
by nearly 180-fold. MOR efficacy and potency in this
series were generally lower than DOR and KOR efficacy
so that overall the TOMI derivatives profiled as mod-
erately selective DOR agonists or partial agonists. The
most promising example was 8d, which had nearly full
agonist activity at DOR with modest efficacy partial
agonism at KOR and MOR. Moreover, the selectivity of
its DOR agonist effects was impressive; 8d as a DOR
agonist was 178 times more potent than as a KOR
partial agonist and 74 times more potent than as a MOR
partial agonist.
On the basis of this in vitro profile, 8d was investi-
gated in vivo in abdominal stretch assays. With phe-
nylquinone (PPQ) as the nociceptor, 8d showed sub-
stantial antinociceptive activity (ED50 ) 5.1 (2.5-9.8)
mg/kg sc), but this was only weakly antagonized by
pretreatment with the selective DOR antagonist NTI
(2a) (maximum antagonism of 40% by 30 mg/kg sc NTI).
Surprisingly the antinociceptive effect of 8d was re-
versed by the MOR antagonist naltrexone. The AD50 of
naltrexone for this reversal (0.02 mg/kg) strongly sug-
gests that the action of 8d in this in vivo assay is
mediated by agonist actions at MOR. 8d was unable to
antagonize the effects of the selective DOR agonist
SNC80 in the PPQ assay when administered sc, but
when administered icv (10µg/brain) 24 h before SNC80
a >50% reversal of the agonist effect was achieved.
type mixed), and the displaced radioligands (DOR, [3H]-
ClDPDPE/[3H]DPDPE; KOR, [3H]U69593/[3H]EKC in
the presence of excess DAMGO) were all different in
the two studies. In [35S]GTPγS assays the DOR selectiv-
ity of 7a as a DOR antagonist (KOR/DOR 26, MOR/DOR
9) was similar to the reported selectivity in isolated
tissue assays (KOR/DOR 28, MOR/DOR 17).12 However,
the DOR antagonist potency of 7a in the GTPγS assay
was 20-fold higher than reported in the mvd assay.
In the present study, there was relatively little SAR
for 1′(N) substitution in TNTI derivatives (7), particu-
larly in the binding assays. Replacement of the 1′-
methyl group in 7a with larger alkyl and arylalkyl
groups generally had little effect on binding affinities
or antagonist potencies for opioid receptors. However,
there were substantial variations in KOR functional
activity in the TNTI series that are surprising and
difficult to explain, particularly when comparing the
methyl (7a) with ethyl (7b) and the benzyl (7d) with
the phenethyl (7f) derivatives. The effect of the ad-
ditional methylene group in both cases was to markedly
enhance KOR efficacy from <20% (antagonism) to >60%
of the efficacy of the standard KOR agonist U69593. The
benzyl to cyclohexylmethyl comparison was similar,
with the effect of reduction of the aromatic ring being
to produce a nearly full KOR agonist (7e) from a KOR
antagonist (7d).
Though there has been considerable investigation of
the effects of piperidine N substitution in epoxymorpi-
nan, morphinan and benzomorphan series,17 comparison
of N-methyl with N-CPM derivatives has not been
thoroughly studied in recent times using modern in vitro
assays. The most consistent and prominent effect of
replacing NMe with N-CPM is a loss of MOR efficacy
with a lesser attenuation of DOR and KOR efficacy.18
In the present study the expected effect on MOR efficacy
was clearly seen in a comparison of TOMI derivatives
(8) with equivalent TNTI derivatives (7); the former
derivatives were all MOR partial agonists, while the
latter derivatives were all MOR antagonists. Substan-
tial loss of DOR efficacy was also observed in the
transformation of 8 to 7, but the effect of the change on
KOR efficacy was dependent on both 17- and 1′-N
substitution. When the 1′-substituent was ethyl, cyclo-
hexylmethyl, or phenethyl, KOR efficacy in the TOMI
series (8) and TNTI series (7) was very similar, whereas
when the 1′-N substituent was methyl or benzyl there
was a dramatic and unexpected loss of KOR efficacy
between 8a,d and 7a,d. The loss of KOR efficacy in the
transformation of the 1′-N-benzyl derivatives 8d to 7d
contrasts with the situation in the 4,5-epoxyphenylpyr-
rolomorphinan derivatives where the 17-methyl and 17-
CPM derivatives with 1′-benzyl substitution (4a, 5) were
KOR antagonists.11 The 1′-N substituted TOMI deriva-
tives (8) in vitro were reasonably potent and somewhat
selective DOR agonists or partial agonists. This activity
was considerably greater than would have been ex-
pected from the report that the equivalent oxymorphin-
dole derivative (3) had neither opioid agonist nor
antagonist activity in isolated tissue assays.7
Discussion
The present study was performed to determine the
SAR for substitution of the pyrrole-N atom in 4,5-
epoxypyrrolomorphinan DOR opioid ligands. Though
the 1′-unsubstituted 4,5-epoxy-4′-phenylpyrrolomorphi-
nan (4d) has been reported,16 it was not possible to
obtain the parent pyrroles 7g and 8g by dealkylation
of the TNTI or TOMI derivatives (7, 8) or by modifica-
tion of the Michael synthesis. We earlier showed that
introducing the 1′(N)-benzyl group into 4d to give 4a
markedly enhanced DOR antagonist activity.11 In the
present study the 1′(N)-methyl (4b) and 1′(N)-ethyl (4c)
analogues had, like 4a, subnanomolar DOR antagonist
potency in the [35S]GTPγS assay and also had similar
DOR selectivity showing that the binding pocket for
antagonist interaction of the 4,5-epoxypyrrolomorphi-
nans with DOR can accommodate small and signifi-
cantly larger 1′(N) substituents equally well. However,
in the receptor binding assays, the smaller 1′(N) sub-
stituents of 4b and 4c were associated with higher
affinity for all three opioid receptor types than the
benzyl group in 4a.
In the absence of the parent TNTI (7g) and TOMI
(8g), the 1′(N)-methyl derivatives 7a and 8a are the
appropriate standards against which to evaluate the
other members of 7 and 8, particularly because 7a had
previously been reported.12 The present data and the
published data for 7a show some very pronounced
differences. It was reported that 7a had high affinity
for DOR (Ki ) 0.54 nM) and a high level of DOR
selectivity (MOR/DOR 311, KOR/DOR 3762) in opioid
receptor binding assays.12 In the present study, the DOR
affinity was about 4-fold lower, but MOR and KOR
affinity was 30- and 500-fold higher, respectively, so that
7a had only marginal binding selectivity for DOR. It is
very difficult to explain such large differences even
though the cell lines (CHO cells/guinea pig brain
membranes), the receptors (recombinant individual/wild
The DOR antagonist activity of the 1′(N)-benzyl TNTI
derivative 7d was confirmed in vivo by the reversal of
the antinociceptive and convulsant effects of the selec-
tive DOR agonist SNC80. This antagonist effect of 7d
administered sc was not particularly impressive, but in
the antinociceptive assay the effect of 7d was equivalent

6648 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 26
Brief Articles
Supporting Information Available: Full experimental
details, including spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
to that of BNTI (2d). Previous reports of the DOR
antagonist activity of BNTI used the icv route.9 The
TOMI derivative 8d showed good antinociceptive activ-
ity in the abdominal stretch assay when administered
sc, but this activity was predominantly the result of a
MOR agonist effect. This was surprising because in the
[35S]GTPγS assays the DOR agonist activity of 8d
appeared to be of higher efficacy and considerably
higher potency than its MOR agonist activity. Though
when administered sc the contribution of a DOR agonist
effect to the antinociceptive effects of 8d was small and
there was no DOR antagonist effect, a distinct DOR
antagonist effect of 8d was observed on icv administra-
tion. Thus, 8d has the profile in vivo of a MOR agonist
when administered peripherally and a DOR antagonist
on central administration. This is similar to our findings
with 1′-benzylnorbinaltorphimine (BnorBNI; 11), which
was a MOR agonist on peripheral administration and
a KOR antagonist on central administration.19
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In conclusion, the previously presented evidence11 for
the enhancement of DOR activity by introduction of a
pyrrolic N-benzyl group in a 4,5-epoxypyrrolomorphinan
series has been confirmed for related series over a
substantial range of N substituents. The TNTI (7) and
TOMI (8) series represent further examples of DOR
ligands of substantial affinity lacking the indolic aro-
matic DOR address system.2,20
Experimental Section
Reagents and solvents were purchased by Aldrich or Lan-
caster and used as received except naltrexone, which was
supplied by the NIDA Drug Supply Program, and oxymor-
phone, which was prepared from oxycodone (Macfarlan Smith
Ltd.) using a standard procedure.21 7 and 8 were prepared
according to the procedure now described for 7d, and com-
pounds of type 4 were prepared using the method described
for 4b.
1′-Benzyl-17-cyclopropylmethyl-6,7-didehydro-3,14-di-
hydroxy-4,5r-epoxy-4′,5′,6′,7′-tetrahydroindolo[2′,3′:6,7]-
morphinan (7d). Benzylamine (0.18 mL, 1.51 mmol) and
p-tolunesulfonic acid monohydrate (1 mg) were added to a
solution of naltrexone (0.50 g, 1.47 mmol) in dry EtOH (1.5
mL) and refluxed in the presence molecular sieves (4 Å) under
nitrogen for 3 h. 1-Nitro-1-cyclohexene (0.17 mL, 1.5 mmol)
was added, and the resulting solution was refluxed for 48 h
before cooling and filtration. The EtOH was removed under
reduced pressure, and the solid obtained was washed with
hexane. Purification of the crude product by column chroma-
tography using 1% MeOH/DCM gave 7d. Yield 0.59 g (80%);
Rf ) 0.64; mp 245 °C; EIMS m/z (% rel intens): 508 (M+, 100),
91 (50). Anal. (C33H36N2O3‚2HCl‚0.75H2O) C, H, N.
17-Cyclopropylomethyl-6,7-didehydro-3,14-dihydroxy-
4,5R-epoxy-1′-methyl-4′-phenylpyrrolo [2′,3′:6,7] morphi-
nan (4b). Methylamine (2 M in MeOH) (2.2 mL, 0.004 mol),
p-toluenesulfonic acid monohydrate (1 mg), and trans-â-
nitrostyrene (0.65 g, 4 mmol) were added to a solution of
naltrexone (1.5 g, 4.0 mmol) in dry EtOH (10 mL) and refluxed
in the presence of molecular sieves (4 Å) under nitrogen for 4
h. It was then cooled and filtered. The EtOH was removed
under reduced pressure, and purification by column chroma-
tography using 0.5% MeOH/DCM gave the required compound
(0.8 g, 40%). TLC (5% MeOH/DCM) Rf ) 0.6; mp 256-260 °C;
MS m/z (rel intens) 454 (M+, 100%). Anal. (C29H30N2O3‚2HCl)
C, H, N.
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Acknowledgment. This work was supported by
NIDA Grant DA 07315. Ligand binding and [35S]GTPγS
assays carried out by NIDA-OTDP, and the in vivo PPQ
assay was performed by the Drug Evaluation Commit-
tee, College on Problems of Drug Dependence.
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