A novel series of hybrid compounds derived by combining 2-aminotetralin and piperazine fragments: Binding activity at D2 and D3 receptors

Article abstract of DOI:10.1016/S0960-894X(01)00820-4

A series of 7-hydroxy-2-[N-alkyl-(N-(4-phenylpiperazine)-alkyl)amino]tetralins was developed based on a novel hybrid approach that combined 2-aminotetralin and arylpiperazine pharmacophoric moieties. Our preliminary study revealed that a four-methylene bu

Full text of DOI:10.1016/S0960-894X(01)00820-4

Bioorganic & Medicinal Chemistry Letters 12 (2002) 619–622
A Novel Series of Hybrid Compounds Derived by
Combining 2-Aminotetralin and Piperazine Fragments:
Binding Activity at D2 and D3 Receptors
Aloke K. Dutta,a,* Xiang-Shu Feia and Maarten E. A. Reithb
aDepartment of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA
bUniversity of Illinois, College of Medicine, Department of Biomedical and Therapeutic Sciences, Peoria, IL 61605, USA
Received 22 August 2001; accepted 30 November 2001
Abstract—A series of 7-hydroxy-2-[N-alkyl-(N-(4-phenylpiperazine)-alkyl)amino]tetralins was developed based on a novel hybrid
approach that combined 2-aminotetralin and arylpiperazine pharmacophoric moieties. Our preliminary study revealed that a four-
methylene butyl linker produced very potent compounds for both the D2 and D3 receptors. Further structure–activity studies led to
a novel template showing 50- to 100-fold selectivity for the D3 receptor. # 2002 Elsevier Science Ltd. All rights reserved.
Enormous progress has been made over the last three
decades in the development of drugs specific for dopa-
mine receptor subtypes and at the same time novel
pharmacology for the characterization of these drugs
has also been developed.1À3 In addition, in 1990a new
subtype of dopamine receptor was discovered which is
now known as D3 receptor, cloned from rat comple-
mentary DNA library using probes derived from the D2
receptor.4,5 This dopamine D3 receptor possesses a high
degree of primary structural homology with the D2
receptor subtype and exhibits similar pharmacological
properties.4 Subsequently, the human version of this
receptor was also cloned.5
selective D3-specific antagonists and agonists are expec-
ted to have therapeutic applications in the treatment of
psychiatric disorders and neurodegenerative diseases
with much less undesirable side effects.8,9 In recent
studies, it has been shown that D3-specific compounds
might have a therapeutic use in the treatment of cocaine
addiction.10À12
Since the discovery of the D3 receptor, substantial
efforts have been directed towards the development of
molecules selective for D3 versus D2 receptors.4 His-
torically 2-aminotetralins have been regarded as potent
and selective agonists for D2-type receptors.13,14
Recently, 7-OH-DPAT and PD 128907 (Fig. 1) were
The problems associated with therapies of neurological
disorders involving D2-specific drugs are the production
of extrapyramidal side effects. These undesirable side
effects are believed to originate in the blockade of D2
receptors in the striatal region of the brain.6 Impor-
tantly, studies showed that the localization of D3 recep-
tors in the brain is different from D2 receptors. In situ
D3 hybridization studies of human brain showed its
dominant presence in the nucleus accumbens area and
islands of Calleja, along with moderate expression in the
caudate and putamen.7 Due to the predominant limbic
location of D3 receptor in the central nervous system,
*Corresponding author. Tel.: +1-313-577-1064; fax: +1-313-577-
2033; e-mail: adutta@wizard.pharm.wayne.edu
Figure 1. Chemical structures of D3 receptor preferring ligands.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00820-4

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A. K. Dutta et al. / Bioorg. Med. Chem. Lett. 12 (2002) 619–622
Scheme 1.
Scheme 2.
evaluated in binding studies for D2 and D3 receptor
subtypes by a number of authors. In general they were
shown to have preferential affinity at the D3 receptor
and the degree of selectivity was dependent upon the
assay conditions, transfected cell lines or tissue used and
the radioligands employed.9,15 Recently a novel series of
arylpiperazine compounds was developed and evaluated
for D2/D3 receptors binding.16,17 Some of these com-
pounds were found to have a high affinity and selectivity
for the D3 receptor. GR103691 was identified as one of
the compounds in this class with high affinity for the D3
receptor.16 In another recent study, a highly selective
ligand 1b (Fig. 1) was developed by incorporating ami-
notetralin and benzamide moieties together.18
pounds with selective affinity for dopaminergic receptor
subtypes. One of our goals was to determine the effect
of different methylene linker size, different aromatic
substitutions, and different substitutions on the N-atom,
upon binding affinity and selectivity for the D3 receptor.
Such structural optimization in these hybrid molecules
may allow interactions with accessory binding sites in
these receptors to impart selectivity. In this report, we
describe the design, synthesis and biological character-
ization of such analogues.
The syntheses of our target compounds are described in
Schemes 1–4.
N-Alkylation of phenylpiperazine with N-(4-bromoalk-
yl)phthalimide in the presence of a base furnished 3a,b
which on reaction with hydrazine produced amines 4a,b.
Reductive amination reaction of amine 4a,b with 7-
methoxytetralone under standard conditions furnished
amines 5a,b in 80–85% yield. N-Alkylation with differ-
ent bromoalkylcyanides resulted in cyano compounds
6a,b which were converted into amines 7a,b by reaction
with lithium aluminum hydride (Scheme 1). Demethyl-
ation of 6a with BBr3 produced the final compound 8.
Conversion of amines 7a,b to benzamide derivatives
followed by demethylation produced the final targets
10a,b (Scheme 2). Similarly, alkylation of 5a,b with
propargyl bromide produced N-alkylated derivatives
which on demethylation produced the final target
compounds 12a,b. N-Acetylation of 5a,b followed by
In our ongoing effort to develop selective and novel
ligands for D2/D3 receptors, we decided to proceed with
a hybrid structure strategy. Thus, we combined the
aminotetralin pharmacophoric fragment with the aryl-
substituted piperazine moiety with varying substitutions
on the N-atom. It was envisioned that incorporation of
the substituted piperazine molecular fragment into the
aminotetralin moiety, as represented in Figure 2, should
produce a novel template for the generation of com-
Figure 2. General structures of the novel molecular template.

A. K. Dutta et al. / Bioorg. Med. Chem. Lett. 12 (2002) 619–622
621
Scheme 3.
Scheme 4.
reduction with lithium aluminum hydride furnished
14a,b. Demethylation of 14a,b produced the final 15a,b
(Scheme 3).19 The dichloro compounds 19a,c were syn-
thesized using the methods described in Schemes 1 and 3
(Scheme 4).
logues for D3 receptors by accessing the additional
binding domains in the receptor, potentially playing a
role in selectivity as well. The design of compound 8
originated from our own results, which demonstrated
that the presence of a cyanopropyl substituent led to an
increase in selectivity for the D3 receptor.20
The activity of the 2-aminotetralin class of compounds
for D2/D3 receptors has been known for some time.
Recently, a novel series of piperazine and modified 2-
aminotetralins was shown to have preferential activity
at the D3 receptor. In our effort to design and develop
new analogues for D2/D3 receptors, we decided to
combine the pharmacophoric elements of 2-amino-
tetralins with piperazine derivatives by a linker to design
a novel series of piperazine moiety derived amino-
tetralin compounds. Our initial effort resulted in the
design and synthesis of two novel compounds, 12b and
15b. In designing 10a,b we decided to incorporate an
additional benzamide moiety into our structural base.
In a recently reported work, it has been demonstrated
that the benzamide derivatives of 2-aminotetralin com-
pounds exhibit preferential affinity for the D3 recep-
tor.18 Thus, it was perceived that an additional amide
linkage should enhance the binding of these novel ana-
These compounds were characterized for their binding
at the cloned human dopamine D2 and D3 receptor
subtypes.21 Compounds 15b and 12b, which contained a
4-methylene-long linker, exhibited weak potency for the
D2 and high affinity for the D3 receptors (Table 1) while
exhibiting moderate selectivity for the D3 receptor. On
the other hand, compound 15a, which contained the 2-
methylene linked carbon chain length, was more selec-
tive and potent at the D3 receptor. As such, 15a was the
most selective compound in its racemic form in this
series. The replacement of the phenyl group in 12b and
15b by a 2,3-dichlorophenyl moiety resulted in 19a,b,
which showed improved potency for the D2 receptor
compared to their unsubstituted phenyl counterparts.
At the same time their potency for the D3 receptor was
unaffected, resulting in lowered selectivity for the D3
receptor. However, compound 19c, which had the two

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A. K. Dutta et al. / Bioorg. Med. Chem. Lett. 12 (2002) 619–622
Table 1. Inhibition constants for binding to the cloned D2L and D3
receptors expressed in HEK cells by displacing [3H]spiperone. Results
are meansÆSEM for three experiments each performed in triplicate
2. Seeman, P.; Tol Van, H. TIPS 1994, 15, 264.
3. Kebabian, J. W.; Calne, D. N. Nature 1979, 277, 93.
4. Sokoloff, P.; Giros, B.; Martres, M.-P.; Bouthenet, M.-L.;
Schwartz, J.-C. Nature 1990, 347, 146.
5. Giros, B.; Matres, M. P.; Sokoloff, P.; Scwartz, J. C. R.
Acad. Sci. [III] 1990, 311, 501.
6. Jenner, P.; Marsden, C. D. In Drugs in Central Nervous
System Disorders; Horwell, D. C., Ed.; Marcel Dekker: New
York, 1985; p 149.
7. Suzuki, M.; Hurd, Y. L.; Sokoloff, P.; Schwartz, J.-C.;
Gordan, S. Brain. Res. 1998, 779, 58.
8. Schwartz, J.-C.; Levesque, D.; Martes, M.-P.; Sokoloff, P.
Clin. Neuropharmacol. 1993, 16, 295.
9. Levant, B. Pharmacol. Rev. 1997, 49, 231.
10. Caine, S. B.; Koob, G. F. Science 1993, 260, 1814.
11. Caine, S. B.; Koob, G. F. Behav. Pharmacol. 1995, 6, 333.
12. Pilla, M.; Perachon, S.; Sautel, F.; Garrido, F.; Mann, A.;
Wermuth, C.; Schwartz, J.-C.; Everitt, B. J.; Sokoloff, P. Nat-
ure 1999, 400, 371.
Compd
D2L HEK Cells
[3H]spiperone
Ki (nM)
D3 HEK Cells
[3H]spiperone
Ki (nM)
D
2L/D3
8
622Æ102
782Æ42
50.2Æ7.1
756Æ48
12.4
1
6.3
17.2
48.9
121.7
30
3.8
10a
10b
12a
12b
15a
15b
19a
19b
19c
354Æ2
55.7Æ5.5
14.2Æ1.7
1.40Æ0.14
1.75Æ0.34
3.79Æ0.40
2.26Æ0.50
3.59Æ0.58
Æ0.04
245Æ26
68.4Æ7.6
213Æ26
114Æ8
8.78Æ0.81
7.37Æ0.27
27.4Æ1.01.13
2.0
24.2
methylene linker chain, was more potent and selective at
the D3 receptor compared to 19a,b. These results are
different from previous observations in a different series
of compounds, indicating that the presence of the 2,3-
dichlorophenyl moiety imparted more selectivity for D3
receptors previously.22
13. Canon, J. G.; Lee, T.; Goldman, H. D.; Costall, B.; Nay-
lor, R. J. J. Med. Chem. 1977, 20, 1111.
14. McDermed, J.; McKenzie, G.; Phillips, A. J. Med. Chem.
1975, 18, 362.
15. Levesque, D.; Diaz, J.; Pilon, C.; Martres, M.-P.; Giros,
B.; Souil, E.; Schott, D.; Morgat, J.-L.; Schwartz, J.-C.;
Sokoloff, P. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 8155.
Burris, K. D.; Pacheco, M. A.; Filtz, T. M.; Kung, M.-P.;
Kung, H. F.; Molinoff, P. B. Neuropsychopharmacology 1995,
12, 335. Audinot, V.; Newman-Tancredi, A.; Gobert, A.;
Rivet, J.-M.; Brocco, M.; Lejeune, F.; Gluck, L.; Desposte, I.;
Bervoets, K.; Dekeyne, A.; Millan, M. J. J. Pharmacol. Exp.
Ther. 1998, 287, 187.
16. Murray, P. J.; Harrison, L. A.; Johnson, M. R.; Robert-
son, G. M.; Scopes, D. I.; Bull, D. R.; Graham, E. A.; Hayes,
A. G.; Kilpatrick, G. J.; Dass, I. D.; Large, C.; Sheehan, M. J.;
Stubbs, C. M.; Turpin, M. P. Bioorg. Med. Chem. Lett. 1995,
5, 219.
17. Teran, C.; Santana, L.; Uriarte, E.; Fall, Y.; Unelius, L.;
Tolf, B.-R. Bioorg. Med. Chem. Lett. 1998, 8, 3567.
18. Homan, E. J.; Copinga, S.; Elfstrom, L.; Veen, T.; Hal-
lema, J.-P.; Mohell, N.; Unelius, L.; Johansson, R.; Wikstrom,
H. V.; Grol, C. J. Bioorg. Med. Chem. 1998, 6, 2111.
19. All new compounds exhibited satisfactory spectral and
elemental analysis data. 7-Hydroxyl-2-[N-propyl-(N-(4-phe-
nylpiperazin-1-yl)-ethyl)amino]tetralin 15a. 1H NMR (CDCl3)
0.86–0.91 (t, J=7.2 Hz, 3H, CH3CH2CH2N), 1.43–1.50(m,
4H), 1.89–1.93 (m, 2H), 2.46–2.51 (t, J=7.5 Hz, 2H, NCH2),
2.53–2.68 (m, 6H), 2.70–2.74 (t, J=4.8 Hz, 4HN(CH2)2), 2.83–
2.88 (m, 1H), 3.23–3.26 (t, J=4.8 Hz, 4H, N(CH2)2), 6.45–
6.56 (m, 2H, Ar-H), 6.83–6.93 (m, 4H, Ar-H), 7.23–7.26 (m,
2H,ꢀAr-H). Free base was converted into its HCl salt, mp 143–
146 C. Anal. (C27H35N3Oꢁ 3HClꢁ 0.9H2O) calcd: C, 57.83; H,
7.72; N, 8.09; Found: C, 57.88; H, 7.52; N, 7.90.
20. Dutta, A. K.; Neisewander, J.; Fuchs, R.; Reith, M. E. A.
Med. Chem. Res. 2000, 10, 208.
The amide piperazines 10a,b had a weak binding affinity
for the dopamine receptor subtypes, while the cyano com-
pound 8 showed some modest binding activity (Table 1).
In this report, we have carried out a brief SAR study
with hybrid piperazine–aminotetralin molecules. Our
results indicated that the compounds with a 2-methyl-
ene linker as in racemic 15a showed high binding activ-
ity at the D3 receptor while being more selective for D3
over D2 receptors. It is evident from our results that the
length of methylene chain linker played an important
role in selectivity. This might indicate subtle differences
in molecular structures between these two receptor sub-
types, which could have been exploited for more favor-
able interactions by the shorter 2-methylene linker
compound with the D3 receptor. We plan to carry out
the functional activities in the future to evaluate for
agonist, antagonist, and partial agonist properties of
these compounds for D2/D3 receptors. We are now
currently exploring this newly developed template to
generate further analogues for selective action at dopa-
mine receptor subtypes.
Acknowledgements
We are grateful to Janet L. Berfield for performing the
DA receptor binding assays, and we thank Dr. Val J.
Watts and Dr. Kim A. Neve at the Oregon Health Sci-
ences University, Portland, OR, for providing us with the
HEK-293 cells stably expressing D2L and D3 receptors.
21. Receptor binding studies were carried out as in ref 20
based on ref 23. Briefly, competition experiments were run
with HEK-293 cell membranes at a final protein concentration
of 25 (D2) or 65 (D3) mg/mL and the radioligand [3H]spiperone
at 0.48 nM (Kd=0.18 nM for D2 and 0.40 nM for D3). Ki
values were calculated from IC50 values by the Cheng–Prusoff
equation as in ref 20.
22. Yuan, J.; Chen, X.; Brodbeck, R.; Primus, R.; Braun, J.;
Wasley, J. F.; Thurkauf, A. Bioorg. Med. Chem. Lett. 1998, 8,
2715.
References and Notes
23. Watts, V. J.; Lawler, C. P.; Knoerzer, T.; Mayleben,
M. A.; Neve, K. A.; Nichols, D. E.; Mailman, R. B. Eur. J.
Pharmacol. 1993, 239, 271.
1. Civelli, O.; Bunzow, J. R.; Grandy, D. K. Annu. Rev.
Pharmacol. Toxicol. 1993, 32, 281.