Potent, orally bioavailable delta opioid receptor agonists for the treatment of pain: Discovery of N,N-diethyl-4-(5-hydroxyspiro-[chromene-2, 4′-piperidine]-4-yl)benzamide (ADL5859)

Article abstract of DOI:10.1021/jm8008986

Selective δ opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable δ agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.

Full text of DOI:10.1021/jm8008986

J. Med. Chem. 2008, 51, 5893–5896
5893
Letters
Chart 1. Structures of 21-23, 1-3
Potent, Orally Bioavailable Delta Opioid
Receptor Agonists for the Treatment of Pain:
Discovery of N,N-Diethyl-4-(5-hydroxyspiro-
[chromene-2,4′-piperidine]-4-yl)benzamide
(ADL5859)
Bertrand Le Bourdonnec,*,† Rolf T. Windh,‡
Christopher W. Ajello,† Lara K. Leister,† Minghua Gu,†
Guo-Hua Chu,† Paul A. Tuthill,† William M. Barker,†
Michael Koblish,‡ Daniel D. Wiant,‡ Thomas M. Graczyk,‡
Serge Belanger,‡ Joel A. Cassel,‡ Marina S. Feschenko,‡
Bernice L. Brogdon,§ Steven A. Smith,§ David D. Christ,§
Michael J. Derelanko,| Steve Kutz,| Patrick J. Little,‡
Robert N. DeHaven,‡ Diane L. DeHaven-Hudkins,‡ and
Roland E. Dolle†
by compounds 21 and 22 can be blocked with δ antagonists in
all species tested, and the absence of these convulsions in mice
lacking the δ receptor strongly suggests the requirement for δ
receptor activation in this effect.15 In contrast to 21 and 22-like
compounds, peptide δ selective agonists have not generally
produced convulsions in rodents.16,17 Furthermore, SB-235863
(23),18 a selective δ agonist of the morphinan class, does not
produce seizures up to 70 mg/kg po and fails to decrease
maximum electroshock seizure threshold (MEST) or potentiate
metrazol-induced seizures.3
Departments of Chemistry, Pharmacology, DMPK, and Preclinical
Safety Assessment, Adolor Corporation, 700 PennsylVania DriVe,
Exton, PennsylVania 19341
ReceiVed July 18, 2008
Abstract: Selective δ opioid receptor agonists are promising potential
therapeutic agents for the treatment of various types of pain conditions.
A spirocyclic derivative was identified as a promising hit through
screening. Subsequent lead optimization identified compound 20
(ADL5859) as a potent, selective, and orally bioavailable δ agonist.
Compound 20 was selected as a clinical candidate for the treatment of
pain.
On the basis of this information, our objective was to identify
a novel series of δ opioid receptor agonists that were not only
potent and highly selective over the µ and κ opioid receptors
but also orally available and, unlike 21 and 22, not convulsive.
A proprietary chemotype, compound 1, was identified as a
promising hit through screening. This agent was subjected to
hit-to-lead, leading to the discovery of the low molecular weight
compound 3 (Chart 1) displaying moderate δ affinity (Ki ) 71
nM), good selectivity over µ and κ opioid receptors, and full δ
agonist activity in vitro (Table 1). Optimization of 3 was then
initiated to further improve the affinity at the δ receptor and
establish nascent SAR in this 4-phenylspiro [chromene-2,4′-
piperidine] series. Compounds 3-20 were tested for their
affinities toward the cloned human δ, κ, and µ opioid receptors
as measured by their abilities to displace [3H]-diprenorphine
from its specific binding sites. The agonist potencies of the target
compounds were assessed by their abilities to stimulate gua-
nosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding to
membranes containing cloned human δ opioid receptors.19 As
indicated in Table 1, introduction of electron withdrawing groups
at the 4′ position of the pendant phenyl group of 3 led to a
substantial improvement in the δ opioid receptor affinity. The
best compound identified from this early lead optimization
campaign was the diethylcarboxamide derivative 11, which
bound to the δ opioid receptor with an affinity of 1.8 nM and
demonstrated greater than 1000-fold selectivity for the δ receptor
compared to the µ and κ receptors. As shown in Table 1,
displacement of the diethylcarboxamide moiety of 11 from the
4′- to the 3′- (12) and 2′-position (13) resulted in a significant
decrease, i.e., 180-fold and 270-fold, respectively, in the δ opioid
receptor affinity. The effect of N-substitution of the piperidine
nitrogen of 11 was then investigated. Substitution of the NH
Endogenous opioid peptides exert their effects through
G-protein-coupled seven transmembrane receptors, designated
µ, κ, and δ opioid receptors. δ selective agonists have
demonstrated efficacy in various animal models of pain.1-5 In
addition, these agents may possess potential clinical benefits
compared with the µ agonists currently used for pain relief,
including reduced respiratory depression,6 constipation,3 physical
dependence,7 and abuse liability.6
A major breakthrough in identifying small molecule non-
peptidic δ agonists was disclosed by Burroughs Wellcome in
1993 with the identification of BW373U86 (21)8 (Chart 1). The
structure-activity relationships (SARa) of this series have
formed the basis of much of the research activity in the area of
δ agonists.9-11 SNC80 (22),12 the optically pure enantiomer of
the methyl ether analogue of 21, exhibits remarkable selectivity
for δ over µ and κ opioid receptors in both receptor binding
and in vitro bioassays.12,13 Unfortunately, 21 and 22 produce
characteristic convulsions in animals at doses similar to the doses
required to elicit analgesic activity.14 The convulsions induced
* To whom correspondence should be addressed. Phone: 1-484-595-1061.
Fax: 1-484-595-1551. E-mail: blebourdonnec@adolor.com.
†
Department of Chemistry, Adolor Corporation.
Department of Pharmacology, Adolor Corporation.
Department of DMPK, Adolor Corporation.
Department of Preclinical Safety Assessment, Adolor Corporation.
‡
§
|
a Abbreviations: SAR, structure-activity relationships; LQT, long QT
syndrome; hERG, human ether-a-go-go related gene; FCA, Freund’s
complete adjuvant; DOR, δ opioid receptor; CYP: cytochrome P450; EEG:
electroencephalogram.
10.1021/jm8008986 CCC: $40.75
2008 American Chemical Society
Published on Web 09/13/2008

5894 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Letters
Table 1. In Vitro Profile of Compounds 3-20 at Opioid Receptors (δ, µ, and κ); Inhibitory Activity of Selected Compounds at the hERG Channela
Ki(µ) (nM) or
%inh.@10 µM
Ki(κ) (nM) or
%inh.@10 µM
IC50(hERG)
(nM)c
compd
R1
R2
R3
Ki(δ) (nM)
EC50(δ) (nM)
3
H
H
H
H
H
H
H
H
H
H
H
H
H
71
(56-89)
72
(40-130)
150
(81-290)
58
(45-74)
59
(30-120)
18
(10-32)
9.3
(3.7-23)
11
(5.5-22)
1.8
(1.1-2.8)
330
(270-400)
480
(310-740)
1300
3.5
(2.3-5.1)
68
(17-270)
360
(100-1300)
1.5
380
(110-1300)
810
(190-3400)
ndb
42 ( 5%
49 ( 8%
42 ( 5%
42 ( 4%
54 ( 3%
60 ( 2%
54 ( 10%
13 ( 1%
32 ( 5%
12 ( 8%
12 ( 8%
3400
(550-21000)
57 ( 7%
680
4
4′-CH3
H
H
H
H
H
H
H
H
H
H
462
5
4′-CF3
2000
(1500-2600)
42 ( 13%
379e
585
6
4′-OCH3
190
(110-350)
220
(110-440)
200
(130-320)
81
(38-170)
220
(140-360)
19
(11-32)
ndb
7
4′-OH
58 ( 8%
63 ( 2%
643e
<100
663
8
4′-CN
9
4′-CO2CH3
4′-CO2H
520
(360-760)
14 ( 7%
10
11
12
13
>100000
7900
303
4′-CON(C2H5)2
3′-CON(C2H5)2
2′-CON(C2H5)2
29 ( 5%
10 ( 4%
45 ( 8%
ndb
6450
14
15
4′-CON(C2H5)2
4′-CON(C2H5)2
H
H
COCH3
CH3
ndb
89
14%
12 ( 6%
2%
24 ( 5%
47440
766
(51-150)
16
17
18
19
20
21
22
4′-CON(C2H5)2
4′-CON(C2H5)2
4′-CON(C2H5)2
4′-CON(C2H5)2
4′-CON(C2H5)2
H
C2H5
H
ndb
13 ( 3%
4 ( 6%
13 ( 2%
28 ( 3%
39 ( 4%
1814
18310
60000
19750
78000
ndb
8-OH
7-OH
6-OH
5-OH
ndb
H
140
(79-240)
1.4
(1.0-2.1)
20
(10-41)
0.40
(0.30-0.52)
10
(6.8-15)
35 ( 0.3%
36 ( 7%
32 ( 3%
(0.54-4.2)
0.43
(0.32-0.58)
0.84
(0.73-0.96)
0.32
(0.25-0.52)
1.2
H
830
(590-1200)
37 ( 2%
H
260
(180-390)
25 ( 3%
130
(71-250)
28 ( 3%
ndb
(0.80-1.7)
a See detailed pharmacological methods in the Supporting Information. b nd: not determined. c Inhibition of hERG channel currents in voltage-clamped
HEK293 cells stably expressing hERG potassium channels; IC50 values are geometric means from at least three separate determinations.
group of 11 with an N-acetyl (14) functionality resulted in a
720-fold decrease in δ receptor binding, suggesting that the basic
nitrogen functionality of 11, protonated at physiological pH, is
an essential pharmacophoric point, presumably involved in
electrostatic interaction with an anionic residue of the δ opioid
receptor. Replacement of the NH group of 11 with an N-methyl
functionality (15) was found to be well tolerated. However,
larger N-substituents resulted in a decrease in the affinity of
the ligand for the δ receptor. As an example, substitution of
the methyl group of 15 with an ethyl moiety (16) resulted in a
20-fold decrease in the δ binding affinity. This SAR distin-
guishes our 4-phenylspiro[chromene-2,4′-piperidine] class of δ
agonists from the compound 22 series.20
long QT syndrome (LQT), which can lead to Torsades de
Pointes, a life threatening form of arrhythmia, and subsequent
ventricular fibrillation.21 Therefore, lead optimization efforts
were focused on further minimizing hERG channel inhibitory
activity while preserving potent affinity at the δ receptor. We
adopted the approach of incorporating polar substituent into the
structure of 11 as a means of controlling log P and to attenuate
hERG inhibitory activity. This strategy has already been
successfully employed in a number of optimization campaigns
designed to reduce the hERG liability of a lead series.22 As
indicated in Table 1, introduction of a hydroxyl group at the
8-position of the spiro[chromene-2,4′-piperidine] core of com-
pound 11 resulted in 200-fold decrease in the affinity toward
the δ opioid receptor. In contrast, the 6- and 5-hydroxy
analogues of compound 11, i.e., compounds 19 and 20
(ADL5859) respectively, displayed subnanomolar binding af-
finity at the δ opioid receptor, potent δ agonist activity, and
excellent opioid receptor selectivity. In addition, 19 and 20
With regard to ancillary activity, we found that 11 moderately
inhibited (IC50 ) 7900 nM) hERG channel currents in vitro
(experiments performed in voltage-clamped HEK293 cells that
stably expressed hERG potassium channels). The blocking of
this cardiac K+ channel (IKr) has been linked to drug-induced

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19 5895
Table 2. Selected Pharmacokinetic Parameters of Compound 20 in Rats
and Dogsa
ratc
dogd
CLs (L/h/kg)
Vdss (L/kg)
t1/2 (oral, h)
Cmax (nM)
F (%)
1.8 ( 0.5
10.7 ( 1.9
5.3 ( 0.7
117 ( 44
33.4 ( 3.2
0.4 ( 0.1
2.5 ( 0.5
b
4.7 ( 0.2
1732 ( 240
66.5 ( 6.8
a Values represent the mean ( standard deviation of three animals.
b Expressed as harmonic mean. c 0.25 mg/kg intravenous and 3.0 mg/kg
oral dose. d 1.0 mg/kg intravenous and 3.0 mg/kg oral dose.
Scheme 1. Synthesis of Compound 20a
Figure 1. Effect of compound 20 in the rat FCA mechanical
hyperalgesia assay. Values on the graph represent the mean and standard
error of the mean (SEM) using n ) 11-12.
a Reagents and conditions: (a) tert-butyl 4-oxopiperidine-1-carboxylate,
pyrrolidine, MeOH, reflux, 75%; (b) MOMCl, iPr2EtN, DCM, reflux, 83%;
(c) C6H5N(SO2CF3)2, LiHMDS, THF, -78 °C to 25 °C, 100%; (d) 4-(N,N-
diethylaminocarbonyl)phenylboronic acid, Pd[P(C6H5)3]4, LiCl, aq Na2CO3,
DME, reflux, 62%; (d) anhyd HCl, dioxane, MeOH, 25 °C, 100%.
rats and dogs was 5.3 and 4.7 h, respectively. There was a
greater than proportional increase in AUC0-∞ with increasing
dose after oral administration of 1-30 mg/kg in rats (data not
shown). The bioavailability of compound 20 (3 mg/kg po) in
rats and dogs was 33% and 66%, respectively. Plasma protein
binding of compound 20 (tested at 2 µM concentration) was
modest in rat (15.9% unbound), dog (15.2% unbound), and
human (41.9% unbound). Compound 20 was moderately
metabolized by human and rat hepatic microsomes, with 64.9%
and 69.2% remaining, respectively, after a 30 min incubation.
Consistent with the low systemic plasma clearance observed in
dog, little metabolism of 20 occurred in dog liver microsomes
(98.7% remaining after 30 min). Compound 20 showed very
little inhibitory activity toward drug-metabolizing CYP enzymes
and was metabolized in vitro by the recombinant human P450
isoenzymes CYP3A4 and CYP2D6. Compound 20 is a selective
δ agonist, as it did not bind to over 100 nonopioid receptors,
channels, or enzymes at a concentration of 10 µM. No overt
side effects of compound 20 have been identified. Only modest
suppression of locomotor activity in rats was produced at a dose
200-fold higher than the ED50 in the FCA assay. Importantly,
no SNC80-like behaviors, including convulsions, increased
locomotor activity, or stereotypic activity, were observed in mice
or rats following administration at po doses of compound 20
up to 1000 mg/kg. No EEG disturbances (seizure-like activity)
were observed following intravenous administration of 10 and
30 mg/kg of compound 20 in a rat EEG telemetry study. These
data highlight a markedly improved CNS safety margin for
compound 20 compared to 22 and representatives of this
chemical class.
Figure 2. Effect of compound 20 in the rat forced swim test. The
data were analyzed by one-way ANOVA with post hoc analysis to
compare the behavioral response after vehicle treatment to the
behavioral response after drug treatment (n ) 12 for each group).
displayed weak inhibitory activity at the hERG channel (19:
hERG IC50 )19.75 µM; 20: hERG IC50 ) 78 µM).
On the basis of their favorable profile in vitro, compounds
19 and 20 were tested in the rat Freund’s complete adjuvant
(FCA) mechanical hyperalgesia assay.23,24 At the screening dose
of 3 mg/kg po, compound 20 produced 100% reversal of
hyperalgesia in the inflamed paw (the paw pressure threshold
of the inflamed paw returned to that of the uninflamed paw). In
contrast, under the same assay conditions, compound 19 when
dosed orally at 3 mg/kg displayed only weak activity (35%
reversal of hyperalgesia). The oral ED50 of compound 20 in
the FCA mechanical hyperalgesia assay was 1.4 mg/kg (Figure
1). The onset of action was rapid after oral dosing of 3 mg/kg,
with significant antihyperalgesia occurring at 30 and 60 min
post-treatment, and the duration of action was relatively short
(less than 60 min; data not shown). The antihyperalgesia
produced by compound 20 (3 mg/kg, po) was reversed by
pretreatment with the δ opioid antagonist naltrindole (0.3 mg/
kg sc), thus demonstrating a δ receptor mediated effect (data
not shown). Several lines of evidence in animal models support
the potential utility of DOR-selective agonists in the treatment
of depression.17,25 In the rat forced swim assay, compound 20
(3 mg/kg po) produced robust antidepressant-like activity, as
evidenced by a significant decrease in the time spent immobile
and a significant increase in the time spent swimming (Figure
2). As was observed for the FCA mechanical hyperalgesia assay,
the effect of compound 20 (3 mg/kg, po) in the forced swim
assay was prevented by pretreatment with naltrindole (1 mg/kg
sc) (data not shown). The pharmacokinetics of compound 20
after iv and po administration to rats and dogs are summarized
in Table 2. The estimated half-life after oral administration in
In summary, starting from a screening hit with submicromolar
affinity at the δ opioid receptor, compound 20, a potent and
highly selective full agonist at the δ opioid receptor that is
structurally distinct from other chemical classes of δ agonists,
was discovered. Compound 20 was prepared as indicated in
Scheme 1. Compound 20 was selected as a clinical candidate
for the management of various pain conditions. In a phase I
safety study conducted in normal healthy volunteers, 20 was
well tolerated and showed good oral exposure with a pharma-
cokinetic profile that may be suitable for once or twice daily

5896 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Letters
dosing.26 Compound 20 has been advanced to phase II proof
Stability. J. Med. Chem. 2000, 43, 3878–3894.
(12) Calderon, S. N.; Rothman, R. B.; Porreca, F.; Flippen-Anderson, J. L.;
McNutt, R. W.; Xu, H.; Smith, L. E.; Bilsky, E. J.; Davis, P.; Rice,
K. C. Probes for narcotic receptor mediated phenomena. 19. Synthesis
of (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-
3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80): a highly selective,
nonpeptide delta opioid receptor agonist. J. Med. Chem. 1994, 37,
2125–2128.
of concept studies for the management of pain.
Acknowledgment. This research was sponsored by Adolor
Corporation. We thank Pfizer for their careful review of the
manuscript.
(13) Calderon, S. N.; Rice, K. C.; Rothman, R. B.; Porreca, F.; Flippen-
Anderson, J. L.; Kayakiri, H.; Xu, H.; Becketts, K.; Smith, L. E.;
Bilsky, E. J.; Davis, P.; Horvath, R. Probes for narcotic receptor
mediated phenomena. 23. Synthesis, opioid receptor binding, and
bioassay of the highly selective delta agonist (+)-4-[(alpha R)-alpha-
((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-
diethylbenzamide (SNC 80) and related novel nonpeptide delta opioid
receptor ligands. J. Med. Chem. 1997, 40, 695–704.
(14) Comer, S. D.; Hoenicke, E. M.; Sable, A. I.; McNutt, R. W.; Chang,
K. J.; De Costa, B. R.; Mosberg, H. I.; Woods, J. H. Convulsive effects
of systemic administration of the delta opioid agonist BW373U86 in
mice. J. Pharmacol. Exp. Ther. 1993, 267, 888–895.
(15) Broom, D. C.; Nitsche, J. F.; Pintar, J. E.; Rice, K. C.; Woods, J. H.;
Traynor, J. R. Comparison of receptor mechanisms and efficacy
requirements for δ-agonist-induced convulsive activity and antinoci-
ception in mice. J. Pharmacol. Exp. Ther. 2002, 303, 723–729.
(16) Tortella, F. C.; Echevarria, E.; Robles, L.; Mosberg, H. I.; Holaday,
J. W. Anticonvulsant effects of mu (DAGO) and delta (DPDPE)
enkephalins in rats. Peptides 1998, 9, 1177–1181.
(17) Vergura, R.; Balboni, G.; Spagnolo, B.; Gavioli, E.; Lambert, D. G.;
McDonald, J.; Trapella, C.; Lazarus, L. H.; Regoli, D.; Guerrini, R.;
Salvadori, S.; Calo, G. Anxiolytic- and antidepressant-like activities
of H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512), a novel selective
delta opioid receptor agonist. Peptides 2008, 29, 93–103.
(18) Dondio, G.; Ronzoni, S. Heterocycle-condensed morphinoid deriva-
tives. Patent WO9602545, 1996.
Supporting Information Available: Experimental procedures
and characterization data for all compounds and experimental
procedure for biological assays. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Fraser, G. L.; Gaudreau, G.-A.; Clarke, P. B. S.; Menard, D. P.;
Perkins, M. N. Antihyperalgesic effects of δ opioid agonists in a rat
model of chronic inflammation. Br. J. Pharmacol. 2000, 129, 1668–
1672.
(2) Brandt, M. R.; Furness, M. S.; Mello, N. K.; Rice, K. C.; Negus, S. S.
Antinociceptive effects of δ-opioid agoists in rhesus monkeys: effects
on chemically induced thermal hypersensitivity. J. Pharmacol. Exp.
Ther. 2001, 296, 939–946.
(3) Petrillo, P.; Angelici, O.; Bingham, S.; Ficalora, G.; Garnier, M.;
Zaratin, P. F.; Petrone, G.; Pozzi, O.; Sbacchi, M.; Stean, T. O.; Upton,
N.; Dondio, G. M.; Scheideler, M. A. Evidence for a selective role in
the δ-opioid agonist [8R-(4bS*, 8aR, 8aꢀ, 12bꢀ)]7,10-dimethyl-1-
methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-
(9H)-4, 8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydro-
chloride (SB-235863) in blocking hyperalgesia associated with
inflammatory and neuropathic pain responses. J. Pharmacol. Exp. Ther.
2003, 307, 1079–1089.
(4) Desmeules, J. A.; Kayser, V.; Guilbaud, G. Selective opioid receptor
agonists modulate mechanical allodynia in an animal model of
neuropathic pain. Pain 1993, 53, 277–285.
(5) Mika, J.; Przewlocki, R.; Przewlocka, B. The role of delta-opioid
receptor subtypes in neuropathic pain. Eur. J. Pharmacol. 2001, 415,
31–37.
(6) Negus, S. S.; Gatch, M. B.; Mello, N. K.; Zhang, X.; Rice, K.
Behavioral effects of the delta-selective opioid agonist SNC80 and
related compounds in rhesus monkeys. J. Pharmacol. Exp. Ther. 1998,
286, 362–375.
(7) Cowan, A.; Zhu, X. Z.; Mosberg, H. I.; Omnaas, J. R.; Porreca, F.
Direct dependence studies in rats with agents selective for different
types of opioid receptor. J. Pharmacol. Exp. Ther. 1988, 246, 950–
955.
(8) Chang, K. J.; Rigdon, G. C.; Howard, J. L.; McNutt, R. W. A novel,
potent and selective nonpeptidic delta opioid receptor agonist
BW373U86. J. Pharmacol. Exp. Ther. 1993, 267, 852–857.
(9) Calderon, S. N.; Coop, A. SNC-80 and related δ opioid agonists. Curr.
Pharm. Des. 2004, 10, 733–742.
(10) Wei, Z.-Y.; Brown, W.; Takasaki, B.; Plobeck, N.; Delorme, D.; Zhou,
F.; Yang, H.; Jones, P.; Gawell, L.; Gagnon, H.; Schmidt, R.; Yue,
S.-Y.; Walpole, C.; Payza, K.; St-Onge, S.; Labarre, M.; Godbout,
C.; Jakob, A.; Butterworth, J.; Kamassah, A.; Morin, P.-E.; Projean,
D.; Ducharme, J.; Roberts, E. N,N-Diethyl-4-(phenylpiperidin-4-
ylidenemethyl)benzamide: A Novel, Exceptionally Selective, Potent
δ Opioid Receptor Agonist with Oral Bioavailability and Its Analogues.
J. Med. Chem. 2000, 43, 3895–3905.
(19) See Supporting Information for assay conditions.
(20) Furness, M. S.; Zhang, X.; Coop, A.; Jacobson, A. E.; Rothman, R. B.;
Dersch, C. M.; Xu, H.; Porreca, F.; Rice, K. C. Probes for Narcotic
Receptor-Mediated Phenomena. 27. Synthesis and Pharmacological
Evaluation of Selective δ-Opioid Receptor Agonists from 4-[(RR)-
R-(2S,5R)-4-Substituted-2,5-dimethyl-1-piperazinyl-3-methoxybenzyl]-
N,N-diethylbenzamides and Their Enantiomers. J. Med. Chem. 2000,
43, 3193–3196.
(21) Pearlstein, R.; Vaz, R.; Rampe, D. Understanding the structure-activity
relationship of the human ether-a-go-go-related gene cardiac K+
channel. A model for bad behavior. J. Med. Chem. 2003, 46, 2017–
2022.
(22) Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. Medicinal
chemistry of hERG optimizations: highlights and hang-ups. J. Med.
Chem. 2006, 49, 5029–5046.
(23) DeHaven-Hudkins, D. L.; Burgos, L. C.; Cassel, J. A.; Daubert, J. D.;
DeHaven, R. N.; Mansson, E.; Nagasaka, H.; Yu, G.; Yaksh, T.
Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with
peripheral selectivity. J. Pharmacol. Exp. Ther. 1999, 289, 494–502.
(24) All housing conditions and experimental procedures were performed
in accordance with the “Guide for the Care and Use of Laboratory
Animals”. Experimental procedures followed the ethical guidelines
of the IASP and were approved by the Adolor Corporation Institutional
Animal Care and Use Committee.
(11) Plobeck, N.; Delorme, D.; Wei, Z.-Y.; Yang, H.; Zhou, F.; Schwarz,
P.; Gawell, L.; Gagnon, H.; Pelcman, B.; Schmidt, R.; Yue, S.-Y.;
Walpole, C.; Brown, W.; Zhou, E.; Labarre, M.; Payza, K.; St-Onge,
S.; Kamassah, A.; Morin, P.-E.; Projean, D.; Ducharme, J.; Roberts,
E. New Diarylmethylpiperazines as Potent and Selective Nonpeptidic
δ Opioid Receptor Agonists with Increased In Vitro Metabolic
(25) Jutkiewicz, E. M. The antidepressant-like effects of delta-opioid
receptor agonists. Mol. InterV. 2006, 6, 162–169.
(26) Clinical studies with 20 are being conducted under open INDs,
indicating FDA approval to conduct clinical studies.
JM8008986