Probes for narcotic receptor mediated phenomena. 26. Synthesis and biological evaluation of diarylmethylpiperazines and diarylmethylpiperidines as novel, nonpeptidic δ opioid receptor ligands

Article abstract of DOI:10.1021/jm9903895

We recently reported (+)-4-[(αR)-α-{(2S,5R)-4-allyl-2,5- dimethyl-1-piperazinyl}-3-methoxybenzyl]-N,N-diethylbenzamide (1b, SNC80) as a novel nonpeptidic δ receptor agonist and explored the structure-activity relationships (SAR) of a series of related der

Full text of DOI:10.1021/jm9903895

J . Med. Chem. 1999, 42, 5455-5463
5455
P r obes for Na r cotic Recep tor Med ia ted P h en om en a . 26.1-3 Syn th esis a n d
Biologica l Eva lu a tion of Dia r ylm eth ylp ip er a zin es a n d Dia r ylm eth ylp ip er id in es
a s Novel, Non p ep tid ic δ Op ioid Recep tor Liga n d s
Xiaoyan Zhang,†,| Kenner C. Rice,*,† Silvia N. Calderon,†, Hiroshi Kayakiri,†,∇ Larren Smith,† Andrew Coop,†,#
Arthur E. J acobson,† Richard B. Rothman,‡ Peg Davis,§ Christina M. Dersch,‡ and Frank Porreca§
Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, Bethesda, Maryland 20892, and Clinical Psychopharmacology Section, National
Institute on Drug Abuse, Addiction Research Center, Baltimore, Maryland 21224, and Department of Pharmacology,
College of Medicine, The University of Arizona, Tucson, Arizona 85724
Received August 2, 1999
We recently reported (+)-4-[(RR)-R-{(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl}-3-methoxyben-
zyl]-N,N-diethylbenzamide (1b, SNC80) as a novel nonpeptidic δ receptor agonist and explored
the structure-activity relationships (SAR) of a series of related derivatives. We have found
that δ binding activities and selectivity showed little change when the 3-methoxy group in 1b
was removed or replaced by the other substituents, whereas the N,N-diethylbenzamide group
is important for interaction with the δ receptor. Extensive modification of the piperazine nucleus
led to the synthesis of a new series of N,N-diethyl(R-piperazinylbenzyl)benzamides (2, 3a -e),
N,N-diethyl(R-piperidinyl or piperidinylidenebenzyl)benzamides (4a , 5a -c, 6a -b), and related
derivatives (4b, 7a -c). Several compounds (2, 3a , 3e, 6a ) strongly bound to the δ receptor
with Ki values in the low nanomolar range. On the other hand, the binding affinities of these
compounds for the µ and κ receptors were negligible, indicating excellent δ opioid receptor
subtype selectivity. The two nitrogen atoms on the piperazine nucleus showed different SAR
in the interaction of this series of compounds at the δ receptor. Nitrogen N4 appears to be an
important structural element and is essential for electrostatic interaction, while N1 seems to
be unnecessary for recognition at the δ receptor.
Classification of opioid receptors into mu (µ), delta (δ),
and kappa (κ) is widely accepted, and they have been
identified by molecular cloning and pharmacological
means.4-6 Recent advances in the understanding of the
physiological functions of the δ opioid receptors have
highlighted the important role of this receptor in the
regulation of pain,7-10 and the search for δ receptor
agonists has been pursued in numerous laboratories. A
number of selective δ agonists, such as DPDPE and
[D-Ala2]deltorphin II, have been developed for probing
the function of the δ receptor.10 Despite their δ agonist
activity, their therapeutic use is limited due to their
peptidic structure. The discovery and identification of
(()-4-[(RR)-R-(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-
3-hydroxybenzyl]-N,N-diethylbenzamide ((()-BW373U86,
(()-1a ) as a selective and nonpeptidic δ receptor agonist
was a major advance in this area.11-13 This compound
has been described as the first systemically active,
nonpeptide δ agonist and has proven useful in the
characterization of the behavioral effects mediated by
central δ receptors in primates.14,15
Recently, we reported the synthesis and absolute
configuration of the optically pure enantiomers of the
nonpeptide δ opioid agonist, (()-1a , its benzylic epimers,
and their methyl ethers.1,2 Among this series, we have
found that replacement of the phenolic hydroxyl group
in 1a with either a methoxyl group ((+)-4-[(RR)-R-
(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-
benzyl]-N,N-diethylbenzamide, 1b, SNC80) or a hydro-
gen atom (1c) gave ligands which retained the potent δ
activities and significantly increased the µ/δ selectivity
in both opioid receptor binding and in vitro functional
assays (Chart 1). Subsequent studies included an in-
vestigation of the role of the amide functional group of
1b-c at the opioid receptors.3 We found that the N,N-
p-disubstituted amide functional group is important for
the interaction of this series of compounds at the δ
receptor. Furthermore, from the above studies we also
learned that the spatial orientation of the R-benzylic
position dramatically influenced the activity and selec-
tivity of these molecules at δ opioid receptors. The
pharmacological profile of compound 1b is similar to (()-
1a in mice, both producing antinociception and mild
transient convulsions at the same dose range.16 How-
ever, compound 1b produces greater antinociceptive
activity in assays of thermal nociception without con-
vulsant activity in the rhesus monkey, suggesting that
† National Institute of Diabetes and Digestive and Kidney Diseases.
‡ National Institute on Drug Abuse.
§ The University of Arizona.
| Present address: Neurogen Inc., 35 NE Industrial Road, Branford,
CT.
Present address: Division of Anesthetic, Critical Care and Abuse
Drug Products, HFD 170, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857.
∇ Present address: Fujisawa Pharmaceutical Co., Ltd., Medicinal
Chemistry Research Laboratories, 2-1-6, Kashima, Yodogawa-ku,
Osaka 532-8514, J apan.
#
Present address: Department of Pharmaceutical Sciences, Uni-
versity of Maryland School of Pharmacy, 20 North Pine St., Baltimore,
MD 21201.
10.1021/jm9903895 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/10/1999

5456 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Ch a r t 1. Structures of δ Opioid Receptor Selective Ligands
Zhang et al.
1
4
1b and related nonpeptidic δ agonists may be promising
candidates for development as safe and effective clinical
analgesics.17 Extensive chemical modifications of this
compound enabled us to further refine the basic frame-
work for the interaction of this series of compounds at
the δ receptor.
reported herein. The newly synthesized analogues were
tested as racemates in order to evaluate the broad effect
of the modification. During this work, similar modifica-
tions were published with comparable results.22-28
Ch em istr y
Most of the nonpeptidic δ opioid ligands (such as
naltrindole and 17-(cyclopropylmethyl)-4,5-R-epoxy-7(E)-
(1-naphthylidene)-3,14-dihydroxymorphinan (BNTX))
contain only one basic nitrogen atom. Site-directed
mutagenesis experiments and molecular modeling stud-
ies have suggested that a basic nitrogen in δ opioid
ligands is an essential structural element for receptor
recognition, although there is conflicting evidence as to
which receptor residue is important for that recog-
nition.18-21 Compound 1b has a carbon-nitrogen skel-
eton that is very different from the well-known fused-
ring opioids, such as naltrindole and BNTX, and thus
any structure-activity relationships dependent upon
the better-known fused-ring opioids may not pertain to
this new structure. Herein, we report our continuing
structure-activity relationship studies of 1b focused on
the investigation of the role of the two basic nitrogen
atoms (N1 and N4) and the influence of substituents on
N4. We initially examined the effects of the trans-
dimethyl groups on the piperazine ring of 1b and found
that piperazine derivative 2, lacking the ring methyl
groups of 1b, retained reasonable δ binding affinity and
µ/δ selectivity. Furthermore, we found that the des-
methoxy analogue 3c shows a similar δ opioid receptor
binding profile as the methoxy analogue 1b. We then
prepared a series of piperazine derivatives with various
substituents on N4 (3a -e). The influence of the two
nitrogens was studied by replacement of one of the
nitrogen atoms (N1 or N4) with carbon (4a , 5a -c, 6a -
b) or oxygen (4b, 7a ). Diarylmethyldiamines (7b-c)
were also prepared to compare the δ activity of 7a . The
synthesis and the structure-activity relationships of
these new compounds on the opioid receptors are
The synthetic intermediates 9-11 were prepared
according to the previously reported method2 or an
alternative pathway26,27 (Scheme 1) more applicable to
the synthesis of these intermediates on a large scale.
Condensation of 4-formylbenzoic acid with diethylamine
in the presence of 1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide (EDCI) gave 4-formyl-N,N-diethylbenz-
amide (8).25 The Grignard reaction of aldehyde 8 with
(3-methoxyphenyl)magnesium bromide provided benz-
hydryl alcohol 9b.2,26 Oxidation of the alcohol 9b with
MnO2 gave the corresponding benzoylbenzamide 11,2,28
while treatment of 9b with concentrated hydrochloric
acid generated the corresponding chloride 8b2 in quan-
titative yield. This newer approach26,27 of preparing
intermediates 9a and 9b offered significant advantages
over the previous one2 in terms of fewer steps, higher
yields, and the easier isolation of the products.
Treatment of the benzhydryl chloride 10a 2 or 10b2
with the appropriate amine yielded the corresponding
analogues 2,23,27 3a -b,27 and 4a -b, as shown in Scheme
1. N-Alkylation of 3a afforded analogues 3c-e.22,25
Compound 7a was synthesized in two steps from ben-
zhydryl alcohol 9b2,26 with chloroethanol, followed by
the displacement of the chloride atom with dimethyl-
amine.
Several approaches different from that of Delorme et
al.24 were examined to construct the diarylmethylpip-
eridines 529,30 (Scheme 2), and only the McMurry
coupling reaction31 of 112,28 with N-benzyl-1-piperidone
gave the desired intermediate 6b24 in reasonable yield
(Scheme 3). Hydrogenation of 6b with a catalytic

Synthesis of Nonpeptidic δ Opioid Receptor Ligands
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5457
Sch em e 1a
a
Conditions: (i) EDCI, Et2NH, CH2Cl2, rt, 97%; (ii) THF, rt, 91%; (iii) H+, 2-chloroethanol, PhCH3, reflux; (iv) HNMe2, K2CO3, KI,
THF, 60-65 °C, sealed, 72%; (v) MnO2, CH2Cl2, 100%; (vi) HCl (conc), CHCl3, 100%; (vii) N-allylpiperazine, K2CO3, CH3CN, 66%; (viii)
K2CO3, CH3CN; (ix) alkyl halide, K2CO3, CH3CN; (x) piperidine, K2CO3, CH3CN, 38%; (xi) morpholine, K2CO3, CH3CN, 78%.
Sch em e 2
amount of Pd/C (10%) in acetic acid yielded a partially
reduced intermediate 6a ,24 which was further reduced
with an equal amount of Pd/C (30%) to give diaryl-
methylpiperidines 5a . Eschweiler-Clarke reaction of 5a
afforded N-methyl analogue 5b, while alkylation of 5a
with allyl bromide provided N-allyl derivative 5c.

5458 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Zhang et al.
Sch em e 3a
a
Conditions: (i) Zn, TiCl4, DME, reflux; (ii) H2 (60 psi), AcOH, Pd/C (10%); (iii) H2 (60 psi), AcOH, Pd/C (30%); (iv) H2CO, HCO2H; (v)
allyl bromide, K2CO3, THF.
Sch em e 4a
consistent with that of Morphy.22,23 Furthermore, in
accord with our findings that the aromatic methoxyl
group of 1b is not essential (its demethoxylated relative
1c had very high affinity for the δ receptor), replacement
of the aromatic methoxyl of 2 with a proton in 3c
increased δ affinity (Ki ) 10.5 nM). Thus, the influence
of the N4 substitution was investigated using this
simplified carbon-nitrogen skeleton. It was shown that
replacement of the N-allyl group with an alkyl moiety
(3b,d ) somewhat reduced affinity at the δ receptor.
However, the N-benzyl derivative 3e had very high
affinity for the δ receptor (Ki ) 1.5 nM), more than twice
the affinity of 1b, in accord with the binding data of
Delorme et al. (1.2 nM).25 It would appear that an
electron rich substituent on N4 leads to increased δ
receptor affinity.
The high affinity of 3e for the δ receptor in this series
is in marked contrast to the observed decrease in affinity
that is obtained when an N-benzyl group is introduced
in naltrindole-like molecules. Thus, 3e, a highly δ-selec-
tive ligand (µ/δ ) >4500, Table 1), was found to have
>70 times higher affinity at the δ receptor than N-
benzyl-substituted oxymorphindole, 17-benzylnoroxy-
morphindole.37 The differences in the δ receptor affinity
between N-substituted naltrindole-like molecules and
compounds similar to 1b could be ascribed to the
distinctively different three-dimensional spatial orienta-
tion of the lone-pair electrons on the nitrogen atom
which have been found in these compounds.38
a
Conditions: (i) 2-(diaminomethyl)ethylamine, benzotriazole,
PhH, reflux; (ii) THF, rt; (iii) H2CO, HCO2H.
The modified Katritzky tertiary amine method32,33
yielded diarylmethyldiamine derivative 7b in a yield of
59%, as illustrated in Scheme 4. Eschweiler-Clarke
reaction of 7b afforded analogue 7c.
Resu lts a n d Discu ssion
All compounds were tested for inhibition of specific
binding of [3H]DAMGO (Tyr-D-Ala-Gly-(Me)-Phe-Gly-
ol)34 to µ receptors and [3H]DADLE (Tyr-D-Ala-Gly-Phe-
D-Leu)35 to δ receptors at rat brain membranes as
previously reported.1-3 The affinity of these derivatives
for κ receptors was determined by inhibition of binding
of [3H]U69,59336 at guinea pig brain membranes. The
values for the µ, δ, and κ receptors are listed in Table
1.
All compounds displayed low affinity at µ and κ
receptors, thus the most δ selective compounds are the
ligands with the greatest δ affinity. The simple dide-
methylpiperazine derivative 2 had about one-seventh
of the δ receptor affinity (δ Ki ) 27 nM) of its trans-
dimethyl relative 1b. The affinity of 2 indicates that
trans-dimethyl groups on the piperazine ring are not
critical for recognition at the δ receptor, a finding
Piperidine analogue 4a and morpholine analogue 4b
showed little or no affinity for the three opioid receptor
subtypes. In contrast, piperidine analogues 5a and 5c
exhibited moderate binding affinity at the δ receptor.
This observed structure-activity relationship suggests
that the basic nitrogen N4 is an important structural
element in the interaction of this series of compounds
at the δ receptor whereas the N1 nitrogen could be
modified while retaining reasonable interaction with the
δ receptor. It should noted that ligands 5a and 5c
possess a methoxy-substituted aromatic ring, whereas
4a and 4b do not, however the SAR above suggest that
this aromatic substituent would not affect affinity to the
extent observed. The poor affinity of 5b is consistent

Synthesis of Nonpeptidic δ Opioid Receptor Ligands
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5459
Ta ble 1. Binding Affinities of Diarylmethylpiperazines and Diarylmethylpiperidines for µ, δ, and κ Receptors
Ki (nM ( SEM)
δ bindingd
Ki ratio
µ/δ
compd
R
X
mp (°C)
formulab
µ bindingc
κ bindinge
1bf
1cg
2
trans-2S,5R-dimethyl-N-allyl-1-piperazinyl OCH3
3970 ( 170
4 ( 0.18
11700 ( 630
3000 (1900)h
10000 (8000)h
990
>3600
>230
trans-2S,5R-dimethyl-N-allyl-1-piperazinyl
N-allyl-1-piperazinyl
H
3000 (1840)h 0.5 ( 0.05
10000 (6300)h 27 ( 2
OCH3 125-127 C26H35N3O2‚
C2H2O4
22H29N3O
C23H31N3O‚
HCl‚2H2O
C25H33N3O‚
HCl‚2.5H2O
3a
3b
N-piperazinyl
N-methyl-1-piperazinyl
H
H
168-169
C
10000 (6800)h 4.85 ( 0.51 ND
>1400
10000 (7000)h
>130
182a
10000 (5600)h 43.2 ( 3
10000 (6600)h 10.5 ( 0.9
10000 (6800)h 44.2 ( 3.9
10000 (6800)h 1.48 ( 0.8
3c
3d
3e
4a
N-allyl-1-piperazinyl
N-propyl-1-piperazinyl
N-benzyl-1-piperazinyl
N-1-piperidinyl
H
H
H
H
H
150a
ND
>600
>150
>4500
>4
170-172 C25 H35 N3O‚
10000 (7000)h
2000 (1400)h
C2H2O4
153-155
125-127
98-100
C
C
C
29H35N3O‚
C2H2O4‚0.25H2O
23H30N2O‚
0.5H2O
22H28N2O2
C24H32N2O2‚
HCl‚H2O
C25H34N2O2‚
HCl‚1.75H2O
C27H36NO2‚
HCl‚0.5H2O
C24H30N2O2‚
HCl‚0.5H2O
C31H36N2O2‚
HCl‚0.5H2O
10000 (6800)h 3000 (1700)h 10000 (7000)h
4b
5a
N-morpholinyl
10000 (6800)h 3000 (1700)h 10000 (7000)h
>4
>300
4-piperidinyl
OCH3 98a
10000 (6300)h 20 ( 2
10000 (6300)h 328 ( 21
10000 (6300)h 27 ( 2
10000 (6300)h 5 ( 0.3
10000 (6300)h 12 ( 1
10000 (6300)h 258 ( 30
10000 (8000)h
10000 (8000)h
10000 (8000)h
5b
5c
6a
6b
7a
N-methyl-4-piperidinyl
OCH3 59a
>15
N-allyl-4-piperidinyl
OCH3 75a
>200
4-piperidinylidene
OCH3 83-85
OCH3 92-95
OCH3 51a
10000 (8000)h >1200
N-benzyl-4-piperidinylidene
2-(N,N-dimethylamino)ethoxy
2-(N,N-dimethylamino)ethamino
7650 ( 429
>500
>20
C23H32N2O3‚
C2H2O4
C31H41N3O10
C24H35N3O2‚
2HCl‚1.5H2O
10000 (8000)h
7b
7c
OCH3 92-94
10000 (6300)h 622 ( 42
10000 (6300)h 248 ( 26
10000 (8000)h
10000 (8000)h
>10
>20
2-(N,N-dimethylamino)-N-methylethylamino OCH3 95-97
a
c
Amorphous powder. bAnalyses for C, H, and N were within (0.4% of the theoretical values. Inhibitory effect to [3H]DAMGO in rat
d
e
brain membranes.
Inhibitory effect to [3H]DADAL in rat brain membranes. Inhibitory effect to [3H]U69,593 in guinea pig brain
membrane. See refs 1 and 2. See ref 2. hNo exact number could be given. The highest concentration tested (nM) is given with the
f
g
maximum binding affinity (nM) in parentheses.
Ta ble 2. Agonist Activity of Selected Compounds in the Mouse Vas Deferens (MVD) and Guinea Pig Ileum (GPI) Bioassay
IC50 (nM ( SEM)
compd
R
X
GPI (µ)
MVD (δ)
µ/δ ratio
1ba
1ca
2
3e
6a
trans-2S,5R-dimethyl-N-allyl-1-piperazinyl
trans-2S,5R-dimethyl-N-allyl-1-piperazinyl
N-allyl-1-piperazinyl
N-benzyl-1-piperazinyl
4-piperidinylidene
OCH3
H
OCH3
H
5450 ( 2050
8580 ( 1300
20300 ( 1300
9850 ( 1050
27700 ( 900
2.73 ( 0.48
10.5 ( 0.4
33.1 ( 3.0
25.7 ( 6.5
125 ( 28
2000
813
610
382
220
OCH3
a
Data from ref 2.
with the findings above that an N4-substituent should
be an electron rich system. When the relative orienta-
tion of the three rings were partially restricted by a
double bond, piperidine 6a exhibited 4-fold higher
affinity at the δ receptor (Ki ) 5 nM) than the unre-
stricted piperidine 5a . Replacement of N1 and N4 with
oxygen led to an ether linked ring-opened analogue 7a ,
which showed decreased affinity at the δ receptor. As
comparison, diarylmethyldiamines 7b and 7c also showed
a considerable loss of affinity at the δ receptor, indicat-
ing that a cyclic amine is required for recognition at the
receptor.
Compounds 2, 3e, and 6a , which possessed good δ
affinity and therefore the greatest δ selectivity in this
series, were evaluated for opioid agonist activity in the
mouse vas deferens (MVD) and guinea pig ileum (GPI)
preparations (Table 2).39 The agonism displayed by
these ligands in the MVD was inhibited by the δ
antagonist, ICI 174,864. Though the current ligands
were less potent δ agonists than the parent compound

5460 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Zhang et al.
mmol) was added portionwise to a cold solution (0 °C) of
4-formylbenzoic acid (21.36 g, 142 mmol), diethylamine (10.41
g, 142 mmol), and triethylamine (20 mL) in 350 mL of
anhydrous CH2Cl2. The mixture was stirred at 0 °C for 30 min
and warmed to the room temperature under Ar. After 4 h, the
reaction was quenched by the addition of 200 mL of saturated
aqueous NaHCO3. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (2 × 100 mL). The combined
organics were washed successively with water, aqueous hy-
drochloric acid (5%), water, and brine, then dried over Na2-
SO4, and concentrated. The product 8 (27.2 g, 93%) was
purified by high vacuum distillation: bp 113-116 °C/0.1
mmHg; 1H NMR δ 1.12 (bs, 3H, CH3), 1.27 (bs, 3H, CH3), 3.22
(bd, J ) 6.84 Hz, 2H, NCH2), 3.57 (bd, J ) 6.84 Hz, 2H, NCH2),
7.53 (d, J ) 8.14 Hz, 2H), 7.93 (d, J ) 8.03 Hz, 2H), 10.05 (s,
1H, CHO); 13C NMR δ 192 (CHO); MS (CI-NH3) m/z 206
(MH+).
Ch a r t 2. Structures of δ Opioid Receptor Selective
Piperidines
1b, all three ligands showed high δ selectivity (GPI/
MVD), which is consistent with the studies in the
binding assays.
4-[Hydr oxy(3-m eth oxyph en yl)m eth yl]-N,N-dieth ylben z-
a m id e (9b).2,26 A solution of 3-(methoxyphenyl)magnesium
bromide was prepared by stirring 3-bromoanisole (11.22 g, 60
mmol) in 120 mL of anhydrous THF with 1.8 g of magnesium
turnings and refluxing for 1 h. The Grignard solution was
cooled, and the clear supernate was transferred into a 500 mL
round-bottom flask equipped with a mechanical stirrer and
reflux condenser via a double-end needle under an atmosphere
of Ar. A solution of 8 (6.15 g, 30 mmol) in 25 mL of anhydrous
THF was added to the Grignard solution via syringe. The
resulting mixture was stirred vigorously for 1 h, and the
reaction was quenched by the addition of 100 mL of saturated
aqueous NH4Cl. The layers were separated, and the aqueous
layer was extracted with Et2O (2 × 100 mL). The combined
organics were dried over MgSO4 and concentrated. The crude
product was crystallized from EtOAc/hexane to yield 8.55 g
(91%) of 9b as white crystals: mp 90-91.5 °C (lit.2 mp 89-90
°C); 1H NMR δ 1.10-1.25 (m, 6H, 2CH3), 2.37 (d, J ) 3.8 Hz,
1H, OH), 3.24 (bs, 2H, NCH2), 3.51 (bs, 2H, NCH2), 3.79 (s,
3H, OCH3), 5.82 (d, J ) 3.26 Hz, 1H, CH), 6.80-6.84 (m, 1H),
6.93-6.95 (m, 2H), 7.23-7.42 (m, 5H).
4-(3-Meth oxyben zoyl)-N,N-d ieth ylben za m id e (11).2,28
To a solution of 9b (10.6 g, 34 mmol) in 200 mL of anhydrous
CH2Cl2 was added activated manganese (IV) oxide (14.8 g, 5
equiv). The resulting mixture was heated at reflux for 3 h
under Ar and then filtered through Celite. The filtrate was
concentrated to give 10.5 g (100%) of 11 as a white solid: mp
88-89.5 °C (lit.2 mp 88-89 °C); 1H NMR δ 1.13-1.28 (bd, 6H),
3.26 (bs, 2H, NCH2), 3.58 (bs, 2H, NCH2), 3.87 (s, 3H, OCH3),
7.15 (dd, J ) 1.96, 6.46 Hz, 1H), 7.27-7.50 (m, 5H), 7.84 (d, J
) 7.92 Hz, 2H).
Con clu sion s
We have investigated a series of N,N-diethyl(R-
piperazinylaryl)benzamides, N,N-diethyl(R-piperidinyl
or piperidinylidenearyl)benzamides, and related deriva-
tives as novel δ opioid receptor ligands. All of these
compounds showed low binding affinity at µ and κ
receptors, and several displayed high binding affinity
at the δ receptor. Two important structure-activity
relationships were observed from this present data: (1)
the alkyl substituent pattern on the nitrogen N4 de-
creased δ binding, and an electron rich substituent aids
interaction with the δ receptor; (2) the nitrogen N4 of
the piperazine is sufficient to provide an essential
electrostatic interaction with the δ receptor; N1 is
relatively unnecessary for binding to the δ receptor.
Recently, it has been reported that a series of N,N-
diethyl(R-piperidinylidenearyl)benzamides 13 (Chart 2),
structurally related analogues of 6a -b , display δ
selective agonism, though the biological activities of
these new compounds were not disclosed.24 Thus, the
N,N-diethyl(R-piperidinylidene-3-methoxybenzyl)benz-
amides 6a -b could be used as a valuable template for
the development of new nonpeptidic ligands for the δ
receptor.
Exp er im en ta l Section .
4-[(4-Allyl-1-p ip er a zin yl)-3-m eth oxyben zyl]-N,N-d ieth -
ylben za m id e (2).23,27 A mixture of 10b2 (1.36 g, 4.13 mmol),
N-allyl-piperazine (0.65 g, 5.15 mmol) and K2CO3 (1.70 g, 12.39
mmol) in 20 mL of anhydrous acetonitrile was heated to reflux
overnight under Ar. The reaction mixture was poured into a
mixture of EtOAc and water. The organic layer was washed
with water, saturated aqueous solution of sodium carbonate
twice and brine, dried over Na2SO4 and evaporated in a
vacuum to give 2 as a colorless oil (1.13 g, 66%): 1H NMR δ
1.12-1.21 (m, 6H), 2.30-2.55 (bs, 8H), 2.99 (d, J ) 6.51 Hz,
2H), 3.21 (bs, 2H), 3.50 (bs, 2H), 3.78 (s, 3H, OCH3), 4.20 (s,
1H, CHN), 5.11-5.20 (m, 2H, CdCH2), 5.75-5.90 (m, 1H, Cd
CH), 6.74-6.75 (m, 1H), 6.97-7.00 (m, 2H), 7.19 (t, J ) 8.1
Hz, 1H), 7.28 (d, J ) 8.4 Hz, 2H), 7.43 (d, J ) 8.1 Hz, 2H); MS
(CI-NH3) m/e 422 (MH+). Compound 2‚oxalate: mp 125-127
°C; Anal. (C26H35N3O2‚C2H2O4) C, H, N.
4-(1-P ip er a zin ylben zyl)-N,N-d ieth ylben za m id e (3a ).27
A mixture of 10a 2 (1.85 g, 6.13 mmol), piperazine (1.58 g, 18.3
mmol), K2CO3 (4.24 g, 30.7 mmol), and anhydrous acetonitrile
(100 mL) was treated in a manner similar to that described
above for the preparation of 2. This gave 1.55 g (72%) of 3a as
colorless crystals: mp 168-169 °C (lit.27 157-169 °C); 1H NMR
δ 1.10 (bs, 3H), 1.20 (bs, 3H), 2.33 (bs, 4H), 2.88 (t, J ) 5 Hz,
4H), 3.25 (bs, 2H), 3.51 (bs, 2H), 4.23 (s, 1H, CHN), 7.16-7.32
(m, 5H), 7.40 (d, J ) 8.0 Hz, 2H), 7.45 (d, J ) 8.0 Hz, 2H); MS
(CI-NH3) m/e 352 (MH+). Anal. (C22H29N3O) C, H, N.
Ch em istr y. Melting points were determined on a MEL-
TEMP II capillary melting point apparatus and are uncor-
rected. Proton nuclear magnetic resonance (1H NMR) spectra
and carbon nuclear magnetic resonance (13C NMR) were
recorded in CDCl3 (unless otherwise noted) with tetrameth-
ylsilane (TMS) as the internal standard on a Varian Gemini-
300 spectrometer. Mass spectra (MS) were recorded on a VG
7070E spectrometer or a Finnigan 4600 spectrometer in the
chemical ionization mode (MS, CI-NH3). Thin-layer chroma-
tography (TLC) was performed on Analtech silica gel GHLF
0.25 mm plates. Flash column chromatography was performed
with Fluka silica gel 60 (mesh 220-240). Elemental analyses
were performed by Atlantic Microlabs. Inc., Norcross, GA, and
the results were within (0.4% of the theoretical values unless
otherwise indicated. Unless specifically indicated otherwise,
amine salts were obtained and purified by the following
standard procedures: (a) hydrochlorides: by the dropwise
addition of 1.0 M HCl/Et2O solution to a solution of the amine
in acetone, until the resulting mixture was acidic to moist pH
paper; (b) maleates and oxalates: by the dropwise addition of
a molar equivalent solution of maleic acid or oxalic acid in
anhydrous Et2O to a solution of the amine in absolute
methanol.
4-F or m yl-N,N-d ieth ylben za m id e (8).25 1-(3-Dimethyl-
aminopropyl)-3-ethylcarbodimide hydrochloride (30.0 g, 157

Synthesis of Nonpeptidic δ Opioid Receptor Ligands
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5461
4-[(4-Met h yl-1-p ip er a zin yl)b en zyl]-N,N-d iet h ylb en z-
a m id e (3b). A mixture of 10a 2 (0.51 g, 1.68 mmol), N-
methylpiperazine (0.19 g, 1.85 mmol), K2CO3 (0.70 g, 5.04
mmol), and anhydrous acetonitrile (5 mL) was treated in a
manner similar to that described above for the preparation of
2. This gave 0.54 g (88%) of 3b as a colorless oil: 1H NMR δ
1.10 (bs, 3H), 1.20 (bs, 3H), 2.28 (s, 3H, NCH3), 2.43 (bs, 8H),
3.24 (bs, 2H), 3.51 (bs, 2H), 4.22 (s, 1H, CHN), 7.17-7.32 (m,
5H), 7.40 (d, J ) 8.0 Hz, 2H), 7.45 (d, J ) 8.0 Hz, 2H); MS
(CI-NH3) m/e 366 (MH+). Compound 3b‚HCl: mp 182 °C
(soften). Anal. (C23H31N3O‚HCl‚2H2O) C, H, N.
4-[(4-Allyl-1-p ip e r a zin yl)b e n zyl]-N ,N -d ie t h ylb e n z-
a m id e (3c).22,27 A mixture of 3a (0.21 g, 0.60 mmol), allyl
bromide (0.09 g, 0.72 mmol), K2CO3 (0.17 g, 1.20 mmol), and
anhydrous acetonitrile (6 mL) was treated in a manner similar
to that described above for the preparation of 2. This gave 0.19
g (81%) of 3c as a colorless oil: 1H NMR δ 1.10 (bs, 3H), 1.20
(bs, 3H), 2.46 (bs, 8H), 3.00 (d, J ) 7.0 Hz, 2H), 3.23 (bs, 2H),
3.51 (bs, 2H), 4.23 (s, 1H), 5.10-5.22 (m, 3H), 5.85-5.87 (m,
1H), 7.19 (dd, J ) 10.0, 7.0 Hz, 1H), 7.24-7.31 (m, 4H), 7.40
(d, J ) 8.0 Hz, 2H), 7.44 (d, J ) 8.0 Hz, 2H); MS m/e calcd for
ether extracts were dried over Na2SO4 and concentrated. The
crude product was purified by acid-base extraction, followed
by chromatography, to yield 1.53 g (65%) of 6b as a light yellow
powder: 1H NMR δ 1.12-1.25 (m, 6H, 2CH3), 2.48 (m, 4H),
2.49 (m, 4H), 3.27 (bs, CONCH2), 3.49-3.54 (m, 4H, CONCH2,
NCH2Ph), 3.76 (s, 3H, OCH3), 6.65-6.78 (m, 3H), 7.13-7.33
(m, 5H); MS m/e calcd for C31H36N2O2: 468.2777, found
468.2763. Compound 6b‚HCl, lyophilizate, mp 92-95 °C (lit.24
100-110 °C. Anal. (C31H36N2O2‚HCl‚0.5H2O) C, H, N.
4-[(4-P ip er id in ylid en e)-3-m et h oxyben zyl]-N,N-d iet h -
ylben za m id e (6a ).24 To a solution of 6b (0.70 g, 1.5 mmol) in
acetic acid (15 mL) was added 70 mg of 10% Pd/C under Ar.
The mixture was subjected to 60 psi of H2 for 24 h. The mixture
was filtered through Celite, and the solvent was evaporated.
The residue was partitioned between 40 mL of saturated
NaHCO3 and 25 mL of CH2Cl2. The aqueous layer was
extracted with CH2Cl2 (3 × 25 mL), and the combined organics
were dried over Na2SO4 and concentrated. The crude product
was filtered through a short silica column, eluting with CHCl3:
CH3OH:NH4OH (100:8:1) to give 0.40 g (70%) of 6a as a
glass: 1H NMR δ 1.21-1.33 (m, 6H, 2CH3), 2.37-2.41 (m, 4H),
2.96-3.00 (m, 4H), 3.36 (bs, 2H, CONCH2), 3.61 (bs, 2H,
CONCH2), 3.85 (s, 3H, OCH3), 6.74-6.87 (m, 3H), 7.22-7.39
(m, 5H); 13C NMR δ 12.77 (CH3), 14.08 (CH3), 33.32, 33.47,
39.12 (CONCH2), 43.28 (CONCH2), 48.44, 55.12 (OCH3),
111.63, 115.76, 122.44, 126.26, 129.09, 129.79, 135.04, 135.16,
137.07, 143.32, 143.63, 159.44, 171.43 (CON); MS (CI-NH3)
m/z 379 (MH+). Compound 6a ‚HCl, lyophilizate, mp 83-85 °C
(lit.24 mp >90 °C (dec)). Anal. (C24H30N2O2‚HCl‚0.5H2O) C, H,
N.
4-[(4-P ip er id in yl)-3-m eth oxyben zyl]-N,N-d ieth ylben z-
a m id e (5a ). To a solution of 6a 24 (1.87 g, 4.0 mmol) in acetic
acid (30 mL) was added 1.87 g of 30% Pd/C under Ar. The
mixture was subjected to 60 psi of H2 for 10 h. The mixture
was filtered through Celite, and the solvent was evaporated.
The residue was partitioned between 40 mL of saturated
NaHCO3 and 40 mL of CH2Cl2. The aqueous layer was
extracted with CH2Cl2 (40 mL × 3) and the combined organics
were dried over Na2SO4 and concentrated. The crude product
was filtered through a short silica column, eluting with CHCl3:
CH3OH:NH4OH (100:15:1) to give 1.25 g (82%) of 5a as a
glass: 1H NMR δ 1.10-1.34 (m, 9H), 1.63 (t, J ) 15.6 Hz, 2H),
2.20-2.27 (m, 2H), 2.61-2.71 (m, 2H), 3.17-3.21 (m, 2H),
3.50-3.54 (m, 3H), 3.79 (s, 3H, OCH3), 6.72-6.75 (m, 1H),
6.82-6.89 (m, 2H), 7.19-7.30 (m, 5H); MS m/e calcd for
C24H32N2O2: 380.2464, found 380.2467. Compound 5a ‚HCl, mp
98 °C (soften). Anal. (C24H32N2O2‚HCl‚H2O) C, H, N.
4-[(1-Meth yl-4-p ip er id in yl)-3-m eth oxyben zyl]-N,N-d i-
eth ylben za m id e (5b). A solution of 5a (0.38 g, 1 mmol) in 1
mL of formic acid (98%) was treated with 1.5 mL of formal-
dehyde aqueous solution (37%) and stirred at 70-80 °C
overnight. The reaction mixture was cooled and basified with
saturated aqueous NaHCO3. The aqueous layer was extracted
with CHCl3 (3 × 10 mL), and the combined organics were dried
over Na2SO4 and concentrated. The crude product was filtered
through a short silica column, eluting with CHCl3:CH3OH:
NH4OH (100:10:1) to give 0.34 g (86%) of 5b as a colorless oil:
1H NMR δ 1.11-1.29 (m, 9H), 1.56 (t, J ) 13.7 Hz, 2H), 1.84-
1.89 (m, 1H), 1.90-2.06 (m, 1H), 2.24 (s, 3H, NCH3), 2.79 (d,
J ) 10.7 Hz, 2H), 3.25 (bs, 2H), 3.45-3.60 (m, 3H), 3.79 (s,
3H, OCH3), 6.70-6.74 (m, 1H), 6.83-6.90 (m, 2H), 7.18-7.32
(m, 5H); MS m/e calcd for C25H34N2O2: 394.2620, found
394.2637. Compound 5b‚HCl: lyophilizate, mp 59 °C (soften).
Anal. (C25H34N2O2‚HCl‚1.75H2O) C, H, N.
C
25H33N3O: 391.2624, found 391.2611. Compound 3c‚HCl: mp
150 °C (soften). Anal. (C25H33N3O‚HCl‚2.5H2O) C, H, N.
4-[(4-P r op yl-1-p ip er a zin yl)b en zyl]-N,N-d iet h ylb en z-
a m id e (3d ).22 A mixture of 3a (0.35 g, 1 mmol), propyl iodide
(0.2 mL, 2 mmol), K2CO3 (0.28 g, 2 mmol), and anhydrous
acetonitrile (20 mL) was treated in a manner similar to that
described above for the preparation of 2. This gave 0.39 g
(100%) of 3d as a colorless oil: 1H NMR δ 0.89 (t, J ) 7.8 Hz,
3H), 1.10-1.20 (m, 6H), 1.46-1.60 (m, 4H), 2.28-2.45 (m, 8H),
3.24 (bs, 2H), 3.51 (bs, 2H), 4.24 (s, 1H, CHN), 7.19-7.29 (m,
5H), 7.38-7.45 (m, 4H); MS (CI-NH3) m/e 394 (MH+).
Compound 3d ‚oxalate: mp 170-172 °C. Anal. (C25H35N3O‚
C2H2O4) C, H, N.
4-[(4-Ben zyl-1-p ip er a zin yl)b en zyl]-N,N-d iet h ylb en z-
a m id e (3e).25 A mixture of 3a (0.20 g, 0.57 mmol), benzyl
chloride (0.13 mL, 1.14 mmol), K2CO3 (0.16 g, 1.14 mmol), and
anhydrous acetonitrile (6 mL) was treated in a manner similar
to that described above for the preparation of 2. This gave 0.20
g (79%) of 3e as a colorless oil: 1H NMR δ 1.00-1.25 (bd, 6H),
2.43-2.48 (m, 8H), 3.24 (bs, 2H), 3.51 (bs, 4H), 4.24 (s, 1H,
CHN), 7.18-7.29 (m, 10H), 7.37-7.44 (m, 4H); MS (CI-NH3)
m/e 442 (MH+). Compound 3e‚oxalate: mp 153-155 °C. Anal.
(C29H35N3O‚C2H2O4‚0.25H2O) C, H, N.
4-[(1-P ip er id in yl)ben zyl]-N,N-d ieth ylben za m id e (4a ).
A mixture of 10a (0.50 g, 1.66 mmol), morpholine (0.4 mL, 4.15
mmol), K2CO3 (0.70 g, 5.04 mmol), and anhydrous acetonitrile
(10 mL) was treated in a manner similar to that described
above for the preparation of 2. This gave 0.22 g (38%) of 4a as
1
colorless crystals: mp 125-127 °C; H NMR δ 1.12-1.25 (m,
6H), 1.42-1.58 (m, 6H, 3CH2), 2.31 (bs, 4H, 2NCH2), 3.26 (bs,
2H, CONCH2), 3.49 (bs, 2H, CONCH2), 4.24 (s, 1H, CHN),
7.19-7.30 (m, 5H), 7-7.44 (m, 4H); MS (CI-NH3) m/e 351
(MH+). Anal. (C23H30N2O‚0.5H2O) C, H, N.
4-[(4-Mor p h olin yl)ben zyl]-N,N-d ieth ylben za m id e (4b).
A mixture of 10a (0.50 g, 1.66 mmol), morpholine (0.4 mL, 4.15
mmol), K2CO3 (0.70 g, 5.04 mmol), and anhydrous acetonitrile
(10 mL) was treated in a manner similar to that described
above for the preparation of 2. This gave 0.45 g (78%) of 4b as
1
colorless crystals: mp 98-100 °C; H NMR δ 1.10-1.25 (m,
6H), 2.36-2.39 (m, 4H, 2NH2), 3.21 (bs, 2H, CONCH2), 3.52
(bs, 2H, CONCH2), 3.69-3.72 (m, 4H, 2OCH2), 4.22 (s, CHN),
7.22-7.31 (m, 5H), 7.40-7.47 (m, 4H); MS (CI-NH3) m/e 353
(MH+). Anal. (C22H28N2O2) C, H, N.
4-[(1-Ben zyl-4-p ip er id in ylid en e)-3-m et h oxyb en zyl]-
N,N-d ieth ylben za m id e (6b).24 Titanium (IV) chloride (2.85
g, 15 mmol) was added to a mechanically stirred suspension
of zinc powder (1.96 g) in dry dimethoxyethane (75 mL) at -10
°C under Ar. When the addition was complete, the mixture
was warmed to room temperature and then refluxed for 2 h.
A mixture of 11 (1.56 g, 5 mmol) and N-benzylpiperidone (0.95
g, 5 mmol) in 25 mL of dimethoxyethane was added to the
cooled suspension of the titanium reagent. The mixture was
refluxed for 4 h, cooled, and poured into 10% aqueous K2CO3
(300 mL). After the mixture was stirred overnight, the aqueous
layer was extracted with Et2O (3 × 100 mL). The combined
4-[(1-Allyl-4-p ip er id in yl)-3-m eth oxyben zyl]-N,N-d ieth -
ylben za m id e (5c). To a solution of 5a (0.40 g, 1.1 mmol) in
10 mL of anhydrous THF were added allyl bromide (0.1 mL,
1.15 mmol) and K2CO3 (0.18 g, 1.3 mmol). The resulting
mixture was stirred at room temperature under Ar. After 4 h,
TLC analysis (CHCl3:CH3OH:NH4OH 90:9:1) showed that no
5a remained. The reaction suspension was filtered, and the
filter cake was washed with CH2Cl2. The filtrate was evapo-
rated and filtered through a short silica column, eluting with
CHCl3:CH3OH:NH4OH (100:3:0.5). The appropriate fractions
were collected and dried under high vacuum to give 0.40 g
(91%) of 5c as a colorless oil: 1H NMR δ 1.12-1.29 (m, 9H),

5462 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Zhang et al.
1.56 (t, J ) 14.6 Hz, 2H), 1.88-2.09 (m, 2H), 2.88 (d, J ) 11.7
Hz, 2H), 2.97 (d, J ) 6.9 Hz, 2H), 3.25 (bs, 2H, CONCH2),
3.46-3.60 (m, 3H), 3.79 (s, 3H, OCH3), 5.10-5.18 (m, 2H, Cd
CH2), 5.81-5.91 (m, 1H, CdCH), 6.70-6.74 (m, 1H), 6.82-
6.89 (m, 2H), 7.18-7.29 (m, 5H); MS m/e calcd for C27H36NO2:
420.2777, found 420.2772. Compound 5c‚HCl: mp 75 °C
(soften). Anal. (C27H36NO2‚HCl‚0.5H2O) C, H, N.
2.17 (s, 3H, NCH3), 2.44-2.46 (m, 4H, 2NCH2), 3.25 (bs, 2H,
CONCH2), 3.51 (bs, 2H, CONCH2), 3.78 (s, 3H, OCH3), 4.35
(s, 1H, NCH), 6.73-6.75 (m, 1H), 6.97-6.99 (m, 2H), 7.19 (t,
J ) 7.8 Hz, 1H), 7.28 (d, J ) 10.8 Hz, 2H), 7.44 (d, J ) 7.8 Hz,
2H); MS (CI-NH3) m/e 398 (MH+). Compound 7c‚HCl, lyo-
philizate, mp 95-97 °C. Anal. (C24H35N3O2‚2HCl‚1.5H2O) C,
H, N.
4-[(2,2-Dim eth yla m in oeth oxy)-3-m eth oxyben zyl]-N,N-
d ieth ylben za m id e (7a ). The benzhydrol 9b was placed in
20 mL of toluene and heated to solution. The solution was
transferred into acidic chloroethanol in 10 mL of toluene and
brought to reflux for 4 h. The reaction was cooled and treated
with 20 mL of saturated aqueous NaHCO3. The layers were
separated, and the aqueous layer was extracted with Et2O (3
× 20 mL). The combined organic were dried over MgSO4 and
concentrated to yield 2.11 g (99%) of 4-[(2-chloroethoxy)-3-
methoxybenzyl]-N,N-diethylbenzamide as a colorless oil: 1H
NMR δ 1.13-1.26 (bd, 6H, 2CH3), 3.27 (bs, 3H, NCH2), 3.54
(bs, 3H, NCH2), 3.67-3.77 (m, 4H), 3.80 (s, 3H, OCH3), 5.41
(s, 1H, OCH), 6.81-6.84 (m, 1H), 6.91-6.94 (m, 2H), 7.23-
7.29 (m, 1H), 7.32-7.41 (m, 4H); MS (CI-NH3) m/z 376 (MH+).
This material was used in the next step.
To a 2.0 M solution of dimethylamine (6 mL, 12 mmol) in
THF were added the chloride from above (0.75 g, 2 mmol), K2-
CO3 (0.276 g, 2 mmol), and KI (0.332 g, 2 mmol). The resulting
mixture was stirred in a sealed tube at 60-65 °C overnight.
The reaction mixture was then cooled and poured into 20 mL
of saturated aqueous NaHCO3 and Et2O (20 mL). The aqueous
layer was extracted with Et2O (2 × 20 mL), and the combined
organics were dried over Na2SO4 and concentrated. The crude
product was filtered through a short silica column, eluting with
CHCl3:CH3OH:NH4OH (100:3:1) to yield 0.554 g (72%) of 7a
as colorless oil: 1H NMR δ 1.11-1.22 (bd, 6H), 2.27 (s, 6H),
2.60 (t, J ) 5.8 Hz, 2H), 3.25-3.59 (m, 4H), 3.79 (s, 3H, OCH3),
5.35 (s, 1H, OCH), 6.78-6.82 (m, 1H), 6.91-6.93 (m, 2H),
7.21-7.39 (m, 5H); MS (CI-NH3) m/z 385 (MH+). The free base
was converted to the oxalate salt (7a ‚oxalate): mp 51 °C
(soften). Anal. (C23H32N2O3‚C2H2O4) C, H, N.
4-[(2,2-Dim eth yla m in oeth yla m in o)-3-m eth oxyben zyl]-
N,N-d ieth ylben za m id e (7b). This material was prepared by
the modified Katritzky tertiary amine method.32,33 A solution
of 3-(methoxyphenyl)magnesium bromide was prepared by
stirring 3-bromoanisole (5 mL, 40 mmol) in 40 mL of anhy-
drous THF with 1 g of magnesium turnings and refluxing for
4 h. The imine adduct 12 was prepared by refluxing N,N-
dimethylethylamine (0.93 g, 10 mmol) and 8 (2.28 g, 10 mmol)
in 30 mL of benzene with a Dean-Stark trap attached to
remove water. After being refluxed for 3 h, the cold solution
of 12 was added dropwise to the Grignard solution, and the
resulting mixture was stirred vigorously under Ar. The reac-
tion mixture was quenched with HCl (10%, 100 mL) at 0 °C.
The acidic aqueous layer was washed (Et2O, 100 mL) and then
carefully basified with aqueous NaOH to pH ∼ 12 at 0 °C. The
basic aqueous layer was extracted with CHCl3 (3 × 100 mL),
and the combined CHCl3 layers were dried over Na2SO4 and
concentrated. The crude product was purified by chromatog-
raphy (silica; CHCl3:CH3OH:NH4OH (100:3:1)) to yield 2.28 g
(59%) of 7b as a glass: 1H NMR δ 1.17-1.22 (bd, 6H), 1.67
(bs, 1H, NH), 1.74 (s, 6H), 2.44 (t, J ) 5.97 Hz, 2H, NCH2),
2.64 (t, J ) 6.30 Hz, 2H, NCH2), 3.25 (bs, 2H, CONCH2), 3.52
(bs, 2H, CONCH2), 3.79 (s, 3H, OCH3), 4.78 (s, 1H, CH), 6.75
(dd, J ) 2.71, 8.04 Hz, 1H), 6.97 (d, J ) 6.51 Hz, 2H), 7.19-
7.31 (m, 3H), 7.42 (d, J ) 8.03 Hz, 2H); MS (CIMS) m/e 384
(MH+). The free base was converted to the maleate salt
(7b‚maleate): mp 92-94 °C. Anal. (C31H41N3O10) C, H, N.
4-[(2,2-Dim et h yla m in o-1-m et h ylet h yla m in o)-3-m et h -
oxyben zyl]-N,N-d ieth ylben za m id e (7c). A solution of 7b
(0.4 g, 1 mmol) in 1 mL of formic acid (96%) was treated with
1.5 mL of formaldehyde aqueous solution (37%) and stirred
at 70-80 °C overnight. The reaction mixture was cooled and
basified with saturated aqueous NaHCO3. The aqueous layer
was extracted with CHCl3 (3 × 10 mL), and the combined
organics were dried over Na2SO4 and concentrated. The crude
product was filtered through a short silica column, eluting with
CHCl3:CH3OH:NH4OH (100:6:1) to give 0.25 g (61%) of 7c as
a glass: 1H NMR δ 1.11-1.25 (bd, 6H), 2.16 (s, 6H, 2NCH3),
Biologica l Assa ys. Ra d ioliga n d Bin d in g Assa ys for µ,
δ, a n d K Recep tor s. µ-Binding sites were labeled using [3H]-
DAMGO (2 nM) and rat brain membranes as previously
described34 with several modifications. Rat membranes were
prepared daily, using a partially thawed frozen rat brain which
was polytroned in 10 mL/brain of ice-cold 10 mM Tris-HCl,
pH 7.0. Membranes were then centrifuged twice, each at
30000g for 10 min. After the second centrifugation, the
membranes were resuspended in 50 mM Tris-HCl, pH 7.4 (50
mL/brain), at 25 °C. Incubations proceeded for 2 h at 25 °C in
50 mM Tris-HCl, pH 7.4, along with a protease inhibitor
cocktail (PIC). The nonspecific binding was determined using
20 µM levallorphan. δ-Binding sites were labeled using [3H]-
DADLE (2 nM) and rat brain membranes as previously
described34 with several modifications. Rat membranes were
prepared daily as with the µ-binding sites, above, except that
incubations proceeded for 2 h at 25 °C in 50 mM Tris-HCl,
pH 7.4, containing 100 mM choline chloride, 3 mM MnCl2, and
100 mM DAMGO to block binding to µ sites, and PIC.
Nonspecific binding was determined using 20 µM levallorphan.
κ1-Binding sites were labeled using [3H]U69,593 (2 nM) as
previously described36 with several modifications. Guinea pig
brain membranes were prepared daily, using partially thawed
guinea pig brain which was polytroned in 10 mL/brain of ice
cold 10 mM Tris-HCl, pH 7.0. Membranes were then centri-
fuged twice, each at 30000g for 10 min. After the second
centrifugation, the membranes were resuspended in 50 mM
Tris-HCl, pH 7.4 (75 mL/brain), at 25 °C. Incubations pro-
ceeded for 2 h at 25 °C in 50 mM Tris-HCl, pH 7.4, containing
PIC and 1 µg/mL of captopril. Nonspecific binding was
determined using 1 µM U69,593. Each [3H] ligand was
displaced by 10 concentrations of test drug, two times. All drug
dilutions were done in 10 mM Tris-HCl, pH 7.4, containing 1
mg/mL bovine serum albumin. All washes were done with ice-
cold 10 mM Tris-HCl, pH 7.4. The IC50 and slope factor (N)
were obtained by using the program MLAB-PC (Civilized
Software, Bethesda, MD). Ki values were calculated according
to the equation Ki ) IC50/(1 + [L]/Kd).
GP I a n d MVD Bioa ssa ys.39 Electrically induced smooth
muscle contraction of mouse vas deferens and strips of guinea
pig ileum longitudinal muscle myenteric plexus were used.
Tissues came from male ICR mice weighing 25-40 g and male
Hartley guinea pigs weighing 250-500 g. The tissues were
tied to gold chain with suture silk, suspended in 20 mL baths
containing 37 °C oxygenated (95% O2, 5% CO2) Krebs bicar-
bonate solution (magnesium free for the MVD), and allowed
to equilibrate for 15 min. The tissues were then stretched to
an optimal length previously determined to be 1 g tension (0.5
g for MVD) and allowed to equilibrate for 15 min. The tissues
were stimulated transmurally between platinum wire elec-
trodes at 0.1 Hz, 0.4 ms pulses (2 ms pulses for MVD), and
supramaximal voltage. Drugs were added to the baths in 14-
60 mM volumes. The agonists remained in contact with the
tissue until maximum inhibition was reached before the
addition of the next cumulative dose. Percent inhibition was
calculated by using the average contraction height for 1 min
preceding the addition of the agonist divided by the contraction
height at maximal inhibition after exposure to the dose of
agonist. IC50 estimates and their associated standard errors
were determined by using a computerized nonlinear least-
squares method.40 Sensitivity to the antagonist ICI-174,864
was tested by adding a 1 µM concentration of the antagonist
to the tissue bath at the completion of the agonist dose-
response curve. Partial or complete restoration of contraction
height on addition of the antagonist was used as an indicator
of the agonistic action at the δ receptor in the case of ICI-
174,864.

Synthesis of Nonpeptidic δ Opioid Receptor Ligands
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5463
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Ack n ow led gm en t. We thank Noel Whittaker and
Wesley White of the Laboratory of Analytical Chemistry
for spectral data. We also acknowledge the National
Institute of Drug Abuse for partial financial support.
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