Synthesis and biological affinity of new imidazo- and indol-arylpiperazine derivatives: Further validation of a pharmacophore model for α1-adrenoceptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.07.084

In the continuing search for selective α₁-adrenoceptor (AR) antagonists, new alkoxyarylpiperazinylalkylpyridazinone derivatives were designed and synthesized. The new compounds were tested for their affinity toward α₁-AR, α₂-AR and 5-HT_1A receptors. The ability of these compounds to inhibit the serotonin transporters (SERT) was also determined. The pharmacological data confirm that increasing the size of the ortho alkoxy substituent on the phenyl ring of the arylpiperazine moiety afforded compounds with enhanced affinity toward the α₁-AR. The isopropoxy group, the largest group evaluated, led the best α₁-AR affinity profile. In contrast, the compounds which have an amide group within of the o-alkoxy-phenylpiperazine fragment showed low affinity toward the receptors studied. Similar results were obtained when the amide group was present in the linker of the junction between the two major constituents of the molecule.

Full text of DOI:10.1016/j.bmcl.2008.07.084

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5140–5145
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological affinity of new imidazo- and indol-arylpiperazine
derivatives: Further validation of a pharmacophore model
for
a
1-adrenoceptor antagonists
a
b
b
Giovannella Strappaghetti a, , Luciano Mastrini , Antonio Lucacchini , Gino Giannaccini ,
*
Laura Betti b, Laura Fabbrini b
a Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, via del Liceo 1, 06123 Perugia, Italy
b Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università degli Studi di Pisa, via Bonanno 6, 56126 Pisa, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
In the continuing search for selective a1-adrenoceptor (AR) antagonists, new alkoxyarylpiperazinylalkylpy-
ridazinone derivatives were designed and synthesized. The new compounds were tested for their affinity
Received 13 May 2008
Revised 18 July 2008
Accepted 19 July 2008
Available online 24 July 2008
toward 1-AR, 2-AR and 5-HT1A receptors.
a
a
The ability of these compounds to inhibit the serotonin transporters (SERT) was also determined. The
pharmacological data confirm that increasing the size of the ortho alkoxy substituent on the phenyl ring
of the arylpiperazine moiety afforded compounds with enhanced affinity toward the
a1-AR. The isopropoxy
Keywords:
group, the largest group evaluated, led the best 1-AR affinity profile. In contrast, the compounds which
a
a
a
1-AR affinity
2-AR affinity
have an amide group within of the o-alkoxy-phenylpiperazine fragment showed low affinity toward the
receptors studied.
5-HT1A affinity
Similar results were obtained when the amide group was present in the linker of the junction between
the two major constituents of the molecule.
Serotonin reuptake inhibitors (SSRI)
6-(Imidazol-1-yl)-pyridazin-3(2H)-one
6-(Indol-1-yl)-pyridazin-3(2H)-one
fragment
Ó 2008 Published by Elsevier Ltd.
Arylpiperazines
Structure–activity relationships (SARs)
a
1-Adrenergic receptors (
a
1-ARs) belong to the seven trans-
has been done and reported, describing synthetic procedures, bio-
membrane-domain receptor super family and play a primary role
in the regulation of several physiological processes, particularly
logical evaluation at the a1-AR and the corresponding subtypes,
and structure-activity relationships (SARs).7
in the cardiovascular system. To date, three different
a
1-AR
We previously reported the synthesis and pharmacological data
of several classes of arylpiperazines, in which an alkoxy-
arylpiperazinylalkylpyridazinone moiety is present as a common
chemical scaffold.8–15 Based on these results, Botta et al.,8,9,11 de-
scribed the construction and validation of a three-dimensional
subtypes, namely, a1A
À
a1B-, and
a1D-AR, have been cloned and
characterized.1,2
In the last years,
a
1-adrenoceptors (a1-AR) have been the sub-
ject of intense research, in part because receptor-binding studies
and molecular biology have opened up new aspects of understand-
ing, but also because of the potential for finding new drugs that
pharmacophore model of a1–AR antagonists sharing a phenylpiper-
azinyl alkyl scaffold as a common structural feature and bearing a
wide variety of heterocyclic moieties at the edge of the alkyl spacer.
The pharmacophoric model8,9,11 that suggests the three-dimen-
could act in pathophysiological processes where
a1-AR are
involved, such as benign prostatic hyperplasia (BPH) or hyperten-
sion.3–6
sional structural properties for an ideal a1–AR antagonist includes:
In this context, the goal of our research was to discover and
(1) A positively ionizable group, corresponding to the more ba-
sic nitrogen atom of the aryl piperazine ring. (2) An ortho- or meta-
substituted phenyl ring, both of which constitute the arylpiper-
azine system and satisfy three of the five features of the pharmaco-
develop novel
for 1-AR and possibly, selectivity toward the
respect to 2-AR or 5-HT1A receptors.
The arylpiperazines are one of the most studied classes of mol-
ecules with affinity at the 1-AR. In fact, a large amount of work
a
1-AR antagonists characterized by a high affinity
a
a1-ARs receptor with
a
phoric hypothesis. (3)
A polar group (corresponding to the
a
pyridazinone ring) that provides a hydrogen bond acceptor feature,
filling one of the portions of the pharmacophore that is required at
the edge of the molecule opposite the arylpiperazine moiety. (4) A
hydrophobic moiety, corresponding to the terminal molecular por-
* Corresponding author. Tel.: +39 075 5855136; fax: +39 075 5855161.
E-mail address: noemi@unipg.it (G. Strappaghetti).
0960-894X/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2008.07.084

G. Strappaghetti et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5140–5145
5141
O
O
OCH3
N
H3CO
N
N
N
N
N
N
N
N
N
N
1
2
tions directly linked to the pyridazinone ring, was hypothesized to
fit one of the five features of the model. The pharmacophoric model
also suggests that the hydrophobic region accommodating the
substituted phenyl can contain constituents that are larger than a
methoxy group. Moreover, affinity and selectivity depend on the
length of the polymethylene chain that connects the pyridazinone
and arylpiperazine moieties. A four carbon-atom spacer is optimal
methoxy group, were substituted at the ortho position of the phe-
nyl ring. This was in agreement with the pharmacophoric model
generated for
a1-AR antagonists that suggested that hydrophobic
groups larger than a methoxy substituent can be accommodated
by a hydrophobic pocket, 8,9,11where the substituted phenyl ring
that is bound to the piperazine lies. For the same objective, an
ortho-alkoxyphenylpiperazine group was replaced by meta-CF3-
phenyl-piperazine group (compounds 5 and 10), to pyrimidin-
piperazine, or a 1-(2,3-dihydro-1,4-benzodioxin-6-yl)piperazine
group (compounds 6, 7, 11, and 12).
for
a1-AR affinity, and a heterocyclic fragment linked to the pyrid-
azinone ring is required at the terminal molecular portion for best
a1-AR affinity.
Based on these considerations, and taking into account our pre-
To confirm the importance of the positively ionizable group,
which corresponds to the more basic nitrogen atom of the pipera-
zine ring, compounds 13, 14, and 15 were synthesized, in which an
amide group was linked to the arylpiperazine fragment. To further
vious experience in this field, compounds 19 and 29 were used as a
template to design compounds 3, 4, 8 and 9.
A spacer of four carbon atoms was maintained in the pipera-
zine-pyridazinone system, and alkoxy moieties, larger than a
investigate if four carbon-atom spacer was indeed optimal for a1
-
R1 = o-OC2H5
20a
20b
20c
R1 = o-OCH(CH3)2
R1 = m-CF3
R1
method A
ì
H
N
N
O
R
Br
R1
N
N
O
N
N
N
N
N
19a
19b
R=
R=
N
N
R1 = o-OC2H5
3
4
N
R =
R
R1 = o-OCH(CH3)2
R1 = m-CF3
N
5
H
N
N
R1 = o-OC H
N
N
H
8
9
10
2
5
N
N
R1 = o-OCH(CH )
N
ììì
20e
R=
3 2
ìì
R1 = m-CF
20d
3
O
O
O
N
N
N
N
O
N
N
O
R
N
N
O
N
N
N
R
6
R=
R=
N
N
N
N
11
7
R=
R=
N
12
Scheme 1. Reagents and conditions: (i) acetonitrile, dry potassium carbonate, 20a, 20b, 20c, reflux; (ii) 20d acetonitrile, dry potassium carbonate, reflux; (iii) butan-2-one,
dry potassium carbonate, reflux.

5142
G. Strappaghetti et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5140–5145
O
R1
N
OH
N
H
N
N
O
N
N
21
R1= OCH3
method B
ìv
20
20a
20b
R1= OC2H5
R1= OCH(CH3)2
O
R1
N
N
O
N
N
N
N
13 R1= OCH3
R1= OC H
14
2
5
R1= OCH(CH )
15
3 2
Scheme 2. Reagents and conditions: (iv) (CDI), CH2Cl2, room temperature.
AR selectivity, compounds 16, 17, and 18, were synthesized, in
which an amide group was present into linker of junction of the
two major constituents of the molecule.
The synthetic pathways to compounds 3–12 are shown in
Scheme 1.
phenyl)piperazin-1-yl]ethanamine 24, 24a, and 24b, respectively,
in the presence of 1-(3-dimethylaminopropyl)N-ethylcarbodimi-
dine hydrochloridre (EDCI), 4-dimethylaminopyridine (DMAP),
and 1-hydroxybenzotriazol-hydrate (HOBt), in dichloromethane
stirred at room temperature under nitrogen atmosphere overnight.
The compounds were purified by column chromatography on silica
gel eluting with CH2Cl2/EtOH. The [3-(imidazol-1-yl)-6-oxo-pyri-
dazin-1(6H)-yl]acetic acid (23) was prepared by alkylation of the
6-imidazoil-pyridazinone9 with ethyl bromoacetate in the pres-
ence of sodium dissolved in dry ethanol. The mixture was refluxed
under stirring for 15 h. After purification by chromatography on
silica gel, the ethyl[3-(imidazol-1-yl)-6-oxopyridazin-1(6H)-
yl]acetate was treated with 5% hydrochloric acid for 2 h at reflux,
after which time, the crystalline acid precipitated in a quantitative
yield (compound 23).
Alkylation of 2-(4-bromobutyl)-6-(imidazol-1-yl)pyridazin-3
(2H)-one (19a), or 2-(4-bromobutyl)-6-(indol-1-yl)pyridazin-
3(2H)-one (19b), synthesized following the previously described
method,9 with 1-(2-ethoxyphenyl)piperazine (20a), 1-(2-isopro-
poxyphenyl)piperazine16 (20b) or with 1-[3-(trifluoromethyl)
phenyl]piperazine (20c), respectively, in acetonitrile in the pres-
ence of dry potassium carbonate, at reflux, afforded the corre-
sponding compounds 3–5 and 8–10. Using the same procedure,
compounds 6 and 11 were made by alkylation starting from 19a
or 19b with pyrimidin-piperazine (20d); compounds 7 and 12
were made by alkylation of compounds 19a or 19b with 1-(2,3-
dihydro-1,4-benzodioxin-6-yl)piperazine (20e) in butan-2-one
and dry potassium carbonate.
1
N
R
The synthesis of compounds 13, 14, and 15 is illustrated in
Scheme 2.
N
The
4-(3-(imidazol-1-yl)-6-oxopyridazin-1(6H)-yl)butanoic
N
O
acid (21) was treated with 1-(2-methoxyphenyl)piperazine (20),
with 1-(2-ethoxyphenyl)piperazine (20a) or with 1-(2-isopropoxy-
phenyl)piperazine16 (20b), respectively, in CH2Cl2 in the presence
of 1-(1H-imidazol-1-yl-carbonyl)-1H-imidazole (CDI) under stir-
ring overnight at room temperature. After evaporation to dryness,
the mixture was purified by column chromatography eluting with
(CH2Cl2/EtOH) to afford the corresponding amides 13–15 as an oil,
in 55–80% overall yield.
N
N
N
HO
24 R1 =OCH3
NH2
23
R1 = OC2H5
24a
method C
v
O
R1 =OCH(CH3)2
24b
1
R
N
Acid 21 was obtained by starting with the condensation of
6-(imidazol-1-yl)pyridazin-3(2H)-one9 with ethyl 4-bromobut-
anoate in acetone/dry potassium carbonate at reflux for 3 h,
the corresponding ester, after purification by column chromatog-
raphy on silica gel, eluting with CH2Cl2/EtOH (96:4), was treated
with 5% hydrochloric acid at reflux for 3 h, after which time, the
crystalline acid was precipitated in a quantitative yield (com-
pound 21).
Compounds 16, 17, and 18 (Scheme 3), containing an amide
group in the linker of the junction of the two major constituents
of the molecule, were prepared by treating the [3-(imidazol-1-
yl)-6-oxopyridazin-1(6H)-yl]acetic acid (23) with 2-[4-(2-alkoxy-
N
N
O
N
N
N
N
H
O
R 1=
R1 =
OCH3
16
17
OC2H5
1
OCH(CH )
18 R =
3
2
Scheme 3. Reagents and conditions: (v) EDCI, DMAP, HOBt, CH2Cl2, room
temperature.

G. Strappaghetti et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5140–5145
5143
Table 1
1-AR,
a
a
2-AR, 5-HT1A serotoninergic receptors and SERT binding affinities of compounds 3–12 and comparison with compounds 1 and 2
R1
O
O
O
O
N
N
N
N
N
N
N
O
N
N
N
N
N
N
N
R
1-5 , 8-10
R
R
6,11
7, 12
Compound
R
R1
Kia (nM)
a
1-AR
a
2-AR
5-HT1A
ndc
SERT
Ratio a2
/
a1
Ratio 5-HT1A/a1
N
1b
o-OCH3
47.5 6.3
0.8 0.4
0.4 0.1
393.0 31.8
147.0 12.0
44.0 4.7
ndc
8.3
ndc
N
N
-
-
3
o-OC2H5
14.0 5.3
6.8 1.1
15%(10
10%(10
l
M) > 10000
163.3
110.0
15.5
17.0
N
N
4
o-OCH(CH3)2
lM) > 10000
N
N
5
m-CF3
118.0 14
0.9 0.1
656.0 170
20.0 4.9
13.0
7
230.0 20
5.6
9.1
N
N
2b
o-OCH3
253.0 24.5
ndc
22.2
281.0
N
N
N
8
o-OC2H5
o-OCH(CH3)2
m-CF3
1.1 0.1
1.7 0.3
60.0 10
70.12 10
20.1 3.3
462.0 240
27.7 0.5
22.8 3.4
62.0 12
639.0 120
1040.0 281
109.0 8.0
62.6
12.0
7.7
24.7
13.6
1.03
9
10
N
6
—
—
710 200
19.0 9.0
1550 70
890.0 260
210.0 70
5%(10
l
M) > 10000
2.2
1.25
11.1
N
N
11
725.0 1.4
25%(10
26%(10
l
M) > 10000
M) > 10000
38.1
N
7
—
—
251.0 80
996.0 50
937.0 270
627.0 64
l
3.9
3.73
44.8
N
N
12
14.0 6.0
476.0 100
4.0 0.3
177 8.0
34.0
[3H]prazosin
0.24 0.05
[3H]rauwolscine
[3H]8-OH-DPAT
[3H]paroxetine
2.0 0.2
0.08 0.2
a
The Ki values are means SD of separate assays, each performed in triplicate. Inhibition constants (Ki) were calculated according to the equation of Cheng and Prusoff:18
Ki = IC50/1+(L/Kd), where [L] is the ligand concentration and Kd its dissociation constant. Kd of [3H]prazosin binding to rat cortex membranes was 0.24 nM (
[3H]rauwolscine binding to rat cortex membranes was 4 nM ( 2), Kd of [3H]8-OH-DPAT binding to rat cortex membranes was 2.0 nM (5-HT1A), and Kd of [3H]paroxetine
a1), Kd of
a
binding to human platelet membranes was 0.08 0.2 nM (SERT).
b
Compounds reported elsewhere by our research group.9
nd: not determined.
c

5144
G. Strappaghetti et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5140–5145
Table 2
a
1-AR, a2-AR, 5-HT1A serotoninergic receptors and SERT binding affinities of compounds 13–18
O
O
H
N
N
N
N
N
N
N
N
N
R1
O
O
R1
N
N
N
N
Compound
R1
Kia (nM)
1-AR
a
a2-AR
5-HT1A
SERT
Ratio a2
/
a1
Ratio 5-HT1A/a1
13
14
15
16
17
18
–OCH3
–OC2H5
–OCH(CH3)2
–OCH3
–OEt
2190 964
492 241
897 342
688 137
234 22
1895 400
1757 273
1343 327
2968 493
3136 327
1956 191
318 79
3%(10
11%(10
2%(10
3464 164
5977 178
>10000
l
l
M) >10000
M) >10000
0.86
3.57
1.49
4.3
13.4
8.89
0.14
4.57
1.73
3.0
4.9
8.7
2250 582
1556 158
2067 318
1150 230
1911 382
lM) >10000
–OiPr
220 44
0.24 0.05
[3H]prazosin
[3H]rauwolscine
[3H]8-OH-DPAT
[3H]paroxetine
4.0 0.3
2.0 0.2
0.08 0.2
a
Each value is the mean SE for data of three different experiments conducted in triplicate. Expressed as Ki, see Refs. 18–20.
Table 3
The pharmacological data expressed in Ki and reported in Table
1 clearly confirm that as the size of the ortho alkoxy substituent on
the phenyl ring of the arylpiperazine moiety increases the affinity
Chemical and physical data of compounds 3–18
Compound
Formula
Mp (°C)
Yield (%)
toward
est group tested, the isopropoxy group (compound 4), gave the
best 1-AR affinity profile (Ki = 0.4 nM). The affinity value was over
100-fold greater than that of the compound in which a methoxy
group was present, (compound 1), with Ki = 47.5 nM. This pharma-
cological profile was inverted when the imidazole group was re-
placed by indole group (compounds 8 and 9). The affinity toward
a1-AR also increases (compounds 3 and 4). In fact, the larg-
3
4
5
6
7
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
26H34Cl2N4O2
27H36Cl2N4O2
22H26Cl2F3N6O
19H27Cl2N8O
23H30Cl2N6O3
28H35Cl2N5O2
29H37Cl2N5O2
27H30 Cl2F3N5O
24H29Cl2N7O
28H33Cl2N5O3
22H28Cl2N6O3
23H30Cl2N6O3
24H32Cl2N6O3
22H29Cl2N7O3
23H31Cl2N7O3
24H33Cl2N4O3
182–188
169–174
164–168
257–260
246–249
149–153
140–145
200–205
225–230
181–185
Hygroscopic
Hygroscopic
Hygroscopic
182–196
178–184
104–108
80
75
42
60
30
85
70
35
49
39
70
64
56
57
25
27
a
8
9
10
11
12
13
14
15
16
17
18
a1–AR decreases when the ortho-alkoxyphenylpiperazine group
was replaced by pyrimidin-piperazine fragment, (compounds 6
and 11) or when this moiety was replaced by a 1-(2,3-dihydro-
1,4-benzodioxin-6-yl)piperazine group (compounds 7 and 12). A
similar reduction in affinity was observed when a meta trifluoro-
methyl group in the piperazine fragment was present (compounds
5 and 10).
Compounds as hydrochlorides, prepared by bubbling dry HCl into the dry ethanol or
diethyl ether solution of the compound.
The
a
2-AR affinity profile of these compounds showed a trend
similar to that found for
a1-AR affinity. In fact, higher affinity
was associated with a bulkier alkoxy constituent at the ortho posi-
tion of the arylpiperazine system, while the affinity decreased
when the ortho-alkoxyarylpiperazine system was replaced by a
1-(2,3-dihydro-1,4-benzodioxin-6-yl)piperazine or a pyrimidin-
piperazine or when a meta-trifluoromethyl group was present in
the arylpiperazine moiety.
A similar pharmacological profile was obtained with the 5-HT1A
receptor. In fact compound 4, with an isopropoxy group present,
showed an interesting affinity for 5-HT1A receptor with a Ki value
of 6.8 nM. A significant decrease in affinity for the 5-HT1A receptor
was observed when the arylpiperazine moiety was replaced
by pyrimidin-piperazine or a 1-(2,3-dihydro-1,4-benzodioxin-6-
yl)piperazine fragment. The low affinity of these compounds for
the SERT suggests that no uptake inhibition is expected with these
derivatives.
The corresponding ethanamines 24, 24a, and 24b were prepared
from 1-phenylpiperazines 20, 20a, and 20b with N-(2-bromoeth-
yl)phthalimide, in the presence of dry potassium carbonate and ace-
tonitrile, under stirring at reflux for 12 h. After purification by
column chromatography on silica gel eluting with CH2Cl2/EtOH,
the corresponding phthalimidoethyl derivatives were treated with
hydrazine hydrate in absolute ethanol at reflux for 3 h.
Synthesized compounds were characterized by 1H NMR, mass
spectra, and elemental analysis, and the analytical data were con-
sistent with the proposed structures.17 The chemical and physical
data for these compounds are reported in Table 3.
The pharmacological profiles of these compounds (reported in
Tables 1 and 2) were evaluated for their affinities toward
a1–AR,
a
2-AR, and 5-HT1A serotoninergic receptors by determining the
It is interesting to note that for compounds 5 and 10, the affinity
toward 5-HT2A was evaluated using [3H]ketanserine as reference
substance. The binding assay was performed in triplicate, with
0.5 nM [3H]ketanserine (Kd = 0.48 0.2) in the absence or presence
ability of each compound to displace [3H]prazosin, [3H]rauwols-
cine, and [3H]8-OH-DPAT, respectively, from specific binding sites
on rat cerebral cortex.18,19
of unlabelled 10 l
M spipern.21 The pharmacological data showed
Moreover, the ability of these compounds to inhibit a serotonin
reuptake in human platelet membranes was determined using
[3H]paroxetine as a reference substance.20
that compound 10 having an indole moiety at the 6-position of
the pyridazinone group had an interesting affinity toward 5-HT2A

G. Strappaghetti et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5140–5145
5145
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with a value data of Ki = 83.0 19 nM, while the affinity decreased
(Ki = 166.0 52) when this group was replaced by an imidazole
fragment (compound 5).
The pharmacological data reported in Table 2 clearly confirm
that the presence of the amide group linked to the arylpiperazine
fragment leads to a marked drop in affinity toward all the receptors
studied (compounds 13, 14, and 15). Similar results were obtained
when this group is present along the length of the alkyl chain that
is used as a spacer between the phenylpiperazine and the terminal
moiety (compounds 16, 17, and 18).
In conclusion, these pharmacological data confirm further on
the pharmacophoric model for a1-antagonist, in fact
(a) An increase in the bulkiness of the alkoxy group at the ortho-
position of the phenyl ring attached to the piperazine fragment
leads to an enhanced affinity toward a1–AR, the isopropoxy group
and a linker of four carbon atoms had the highest affinity of the
compounds tested. (b) It was confirmed that a meta-substitution
or the presence of the pyrimidin-piperazine, or 1-(2,3-dihydro-
1,4-benzodioxin-6-yl)piperazine fragment, leads to a marked drop
in affinity toward a1–AR. (c) The presence of an amide in the alkyl
chain that is used as a spacer between the phenylpiperazine and
12. Betti, L.; Floridi, M.; Giannaccini, G.; Manetti, F.; Strappaghetti, G.; Tafi, A.;
Botta, M. Bioog. Med. Chem. Lett. 2003, 13, 171.
13. Betti, L.; Corelli, F.; Floridi, M.; Giannaccini, G.; Maccari, L.; Manetti, F.;
Strappaghetti, G.; Botta, M. J. Med. Chem. 2003, 46, 3555.
14. Betti, L.; Floridi, M.; Giannaccini, G.; Manetti, F.; Paparelli, C.; Strappaghetti, G.;
Botta, M. Bioorg. Med. Chem. 2004, 12, 1527.
15. (a) Betti, L.; Zanelli, M.; Giannaccini, G.; Manetti, F.; Schenone, S.;
Strappaghetti, G. Bioog. Med. Chem. 2006, 14, 2828; (b) Strappaghetti, G.;
Brodi, C.; Giannaccini, G.; Betti, L. Bioog. Med. Chem. Lett. 2006, 16,
2575.
16. Martin, G. E.; Elgin, R. J.; Mathiasen, J. R.; Davis, C. B.; Kesslick, J. M.; Baldy, W.
J.; Shank, R. P.; Di Stefano, D. L.; Fedde, C. L.; Scott, M. K. J. Med. Chem. 1989, 32,
1052.
the terminal moiety leads to a marked drop in affinity toward
a1–AR. (d) Finally it is confirmed that the presence of an amide
group linked to the arylpiperazine fragment showed low affinity
toward all the receptors studied, confirming the importance of
the positively ionizable group, corresponding to the more basic
nitrogen atom of the piperazine ring.
17. C, H, and
N analysis of these compounds gave results within 0.4% of
theoretical values. 1H NMR mass spectra are consistent with the assigned
structures of compounds 3–18.
18. Cheng, Y. C.; Prusoff, W. H. Biochem. Pharmacol. 1973, 22, 3099.
19. Lowry, O. H.; Rosenbrough, N. J.; Farr, A. L.; Randall, R. J. J. Biol. Chem. 1951, 19,
3265.
References and notes
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