Synthesis and theoretical study of 2-amino-2,3,3a,4,5,6-hexahydro-1H-phenalene and its biological evaluation on central dopaminergic system

Article abstract of DOI:10.1016/S0014-827X(00)00081-1

Compound 2 considered as a rigid non-hydroxylated 2-amino tetralin was synthesized and biologically evaluated. Central administration of compound 2 (50 μg or 100 μg/10 μl) induced a reduction in urinary sodium and potassium excretion at 3 and 6 h of urine collection. We speculate that compound 2 may be acting as a dopamine receptor antagonist.

Full text of DOI:10.1016/S0014-827X(00)00081-1

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 575–582
Synthesis and theoretical study of
2-amino-2,3,3a,4,5,6-hexahydro-1H-phenalene and its biological
evaluation on central dopaminergic system
J.E Angel-Gu´ıo a,*, J.E. Charris d, J. Pe´rez d, Z. Duerto de Pe´rez d, R. Compagnone d,
A. Israel b, L. Orfila b, B. Migliore de Angel a, S.E. Lo´pez c, L. Rodr´ıguez e,
J. Caldera a, E. Michelena de Ba´ez a, F. Arrieta a
a Laboratorio de S´ıntesis Orga´nica y Disen˜o Molecular, Departamento de Qu´ımica, Facultad Experimental de Ciencias, Uni6ersidad del Zulia,
Maracaibo, Venezuela
b Laboratorio de Neurope´ptidos, Facultad de Farmacia, Uni6ersidad Central de Venezuela, Caracas, Venezuela
c Departamento de Qu´ımica, Laboratorio de Qu´ımica Orga´nica 210, Uni6ersidad Simo´n Bol´ı6ar, Venezuela
d Laboratorio de S´ıntesis Orga´nica, Facultad de Farmacia, Uni6ersidad Central de Venezuela, Caracas, Venezuela
e Laboratorio de Qu´ımica Teo´rica y Computacional, Departamento de Qu´ımica, Facultad Experimental de Ciencias, Uni6ersidad del Zulia,
Maracaibo, Venezuela
Received 30 November 1999; accepted 10 July 2000
Abstract
Compound 2 considered as a rigid non-hydroxylated 2-amino tetralin was synthesized and biologically evaluated. Central
administration of compound 2 (50 mg or 100 mg/10 ml) induced a reduction in urinary sodium and potassium excretion at 3 and
6 h of urine collection. We speculate that compound 2 may be acting as a dopamine receptor antagonist. © 2000 Elsevier Science
S.A. All rights reserved.
Keywords: Antagonist; Receptor; Dopamine
was synthesized as a rigid non-hydroxylated amino
indan and evaluated biologically. The results showed
that 1 is a novel compound that acts on the dopaminer-
gic central system [6,7] and also as a MAO-enzyme
inhibitor [8]. As a consequence in the present study, we
show the synthetic pathway for the preparation of the
1. Introduction
The central nervous system (CNS) dopaminergic sys-
tem in mammalian brain has been the subject of exten-
sive studies in the past two decades. Dopamine (DA)
systems and their associated receptors in the brain are
important in modulating motor, endocrine and emo-
tional functions [1,2]. Furthermore, both DA neurons
and DA receptors are markedly reduced by normal
aging and Parkinson’s disease [3,4] and have been im-
plicated in a variety of other disorders, including
schizophrenia and drugs abuse [5]. Structure–activity
relationship studies of many classes of dopamine recep-
tor agonists allow some generalization regarding do-
paminergic activity. Considering this fact, compound 1
2-amino-2,3,3a,4,5,6-hexahydro-1H-phenalene (2),
a
non-hydroxylated rigid derivative of 2-aminotetralin
which possess inside its structure, the partial fragment
of the dopaminergic receptor pharmacophore
(phenylethylamino) and an additional carbon atom
with respect to compound 1. On the other hand, it has
been shown that compound 3 is an agonist of the D-2
receptor [9] and its skeleton is an isoster of the
phenalene nucleus present in 2. Taking the above-men-
tioned aspects into consideration, we propose that com-
pound 2 should show a similar biological activity as
compound 1, possibly through a dopaminergic mecha-
nism (Fig. 1).
* Corresponding author.
E-mail address: jangel@luz.ve (J.E. Angel-Gu´ıo).
0014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(00)00081-1

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J.E. Angel-Gu´ıo et al. / Il Farmaco 55 (2000) 575–582
phoric acid method to give ketone 8 [12]. In the first
2. Chemistry
approach, route A (Scheme 2), for the introduction of
the amino group at the a position of ketone 8, a
bromination reaction with pyridinium hydrobromide
perbromide in CHCl3 was carried out. The resulting
a-bromoketone 9 was later converted into the azide
derivative 10 by a treatment with NaN3 in aqueous
DMF. Subsequent catalytic hydrogenation of 10 in
acidic medium (HCl–EtOH) over 10% Pd–C followed
by reduction with NaBH4, afforded the desired amino
alcohol 12 with an overall yield of 38% from 8 [13].
Another but less efficient route B was used to prepare
this key intermediate 12, where the formation of the
keto oxime 13 is involved through the treatment of
compound 8 with n-butyl nitrite in basic medium using
sodium t-butoxide [14]. Subsequent catalytic reduction
in solution of HCl–EtOH over 10% Pd–C afforded the
desired amino alcohol 12 with an overall yield of 16%
from 8 [15]. As the last step, a catalytic reduction of 12
with a mixture of acetic and sulfuric acids over 10%
Pd–C gave the final compound 2 as a diasteromeric
mixture [7].
The 2-amino-2,3,3a,4,5,6-hexahydro-1H-phenalene
(2) have been prepared following the steps depicted in
Schemes 1 and 2 by the intermediacy of the unknown
amino alcohol 12 obtained in two ways (Scheme 2). In
order to have access to this latter derivative, we started
from the condensation of the a-tetralone 4 with diethyl
succinate using sodium t-butoxide as the condensing
agent. Following, the half ester 5 was decarbethoxy-
lated by the action of a mixture of hydrochloric and
acetic acids to give the unsaturated acid 6 [10]. Cata-
lytic hydrogenation of 6 afforded the known 1,2,3,4-te-
trahydro-1-naphthyl-propionic acid (7) [11]. Cyclization
of this latter acid 7 proceeded rapidly by the polyphos-
3. Experimental
3.1. Chemistry
Uncorrected melting points were determined using a
1
Thomas Hoover capillary melting point apparatus. H
Fig. 1. Structures of compounds 1–3.
NMR spectra were recorded using a JEOL GSX (270
MHz) and reported in ppm (l) downfield from TMS as
an internal standard. Infrared spectra were determined
as KBr pellets on a Shimadzu model 470 spectrophoto-
meter. Carbon, Hydrogen and Nitrogen elemental
analyses were performed by Atlantic Microlab Labora-
tories, Atlanta, GA, and were within 90.4% of the
theoretical values. Mass spectra were recorded on a
Hewlett–Packard 5995 mass spectrometer. The purity
of all compounds was assessed by thin layer chro-
matography using several solvents of different polarity.
All solvents were distilled and dried in the usual
manner.
3.1.1. i-Carbetoxy-i-(3,4-dihydro-1-naphtyl)-propionic
acid (5)
A solution of a-tetralone 4 (14.6 g, 0.1 mol), ethyl
succinate (26.1 g, 0.15 mol) in t-butyl alcohol (20 ml)
was added to a solution of metallic sodium 2.6 g (0.11
mol) in t-butyl alcohol (40 ml). The resulting mixture
was refluxed for 4 h. After cooling, the mixture was
acidified using diluted hydrochloric acid (10%) under
vigorous stirring. The organic phase was extracted with
diethyl ether. The organic extract was washed several
times with sodium bicarbonate (10%) and water. The
organic extracts were dried over anhydrous magnesium
Scheme 1. Synthetic pathway of compound 8. Reagents: (a)
EtO2CꢀCH2ꢀCH2ꢀCO2Et,
NaOC(CH3)3,
HOC(CH3)3/D;
(b)
HClꢀAcOHꢀH2O/D; (c)H2/10% Pd–C–ethanol; (d) PPA, 60°C.

J.E. Angel-Gu´ıo et al. / Il Farmaco 55 (2000) 575–582
577
Scheme 2. Synthetic pathway of compound 2. Reagents: (a) Py+HBr3–CHCl3 50°C; (b) NaN3ꢀDMFꢀH2OꢀAcOH; (c) H2/10% Pd–C EtOHꢀHCl;
(d) NaBH4ꢀMeOH; (e) n-BuONOꢀNaOCMe3ꢀHOCMe3; (f) H2/10% Pd–C HClꢀEtOH; (g)) H2/10% PdꢀC AcOHꢀH2SO4.
sulfate. The solvent was removed under reduced pres-
sure to give a red crude (22 g) that later turned brown
(m.p. 65–70°C). Recrystallization of the crude product
from ethanol–water produced a white solid (17 g,
65%), m.p. 68–69°C (Lit. [10] m.p. 64–69°C). IR (KBr,
cm−1): 3311–2138 (COOH), 1711 (CO). 1H NMR
(CDCl3): 1.00 (t, 3H, CH3CH2O), 1.78 (m, 2H,
ArCH2CH2), 2.00–2.78 (m, 4H, CH2COOH,
ArCH2CH2), 3.26 (m, 1H, CCHCO), 3.94 (m, 2H,
CH3CH2O), 5.78 (t, 1H, ꢁCH), 6.73–7.31 (m, 4H,
ArH), 10.73 (s, 1H, CO2H).
3.1.2. i-(3,4-Dihydro-1-naphtyl)-propionic acid (6)
A solution of compound 5 (18 g, 0.06 mol), in acetic
acid (126 ml), hydrochloric acid (63 ml), and water (90
ml), was refluxed for 24 h. During the first 3 h of
heating, evolution of CO2 was observed. The mixture
was concentrated under reduced pressure. To the
semisolid residue, extracted with diethyl ether, diluted
solution of sodium hydroxide was added. The resulting
basic solution was acidified using concentrated sulfuric
acid to give a brown solid that recrystallized from
ethanol–water. 83% Yield; m.p. 105–107°C; (Lit. [10]

578
J.E. Angel-Gu´ıo et al. / Il Farmaco 55 (2000) 575–582
106.8–107.5°C). IR (KBr, cm−1): 3500–2000 (COOH),
1703 (CO). 1H NMR (CDCl3): 2.00–2.52 (m, 2H,
ArCH2CH2Cꢁ), 2.52–3.79 (m, 6H, ꢁCCH2CH2CO,
ꢁCCH2CH2CO, ArCH2CH2Cꢁ), 5.89–6.21 (m, 1H,
ArCꢁCH), 7.10–8.47 (m, 4H, ArH), 11.26 (s, 1H,
COOH).
after extraction with diethyl ether and evaporation of
the solvents gave a solid that was recrystallized from
acetone–water. 20% yield of a red precipitate, m.p.
144–145°C. IR (KBr, cm−1): 3600–3046 (OH), 1679
(CO). 1H NMR (DMSO-d6): 0.68–2.26 (m, 4H,
CH2CH2), 2.47–3.10 (m, 3H, ArCH2, ArCH), 3.21–
3.73 (m, 2H, CH2CꢁNOH), 6.84–7.36 (m, 3H, ArH),
7.36–7.94 (bb, 1H, ꢁNOH).
3.1.3. i-(1,2,3,4-Tetrahydro-1-naphtyl)-propionic acid
(7)
3.1.6. 2-Bromo-2,3,3a,4,5,6-hexahydro-1H-phenalen-
1-one (9)
Compound 6 (2.5 g, 12,3 mmol), was hydrogenated
over 10% Pd–C (0.25 g) in ethanol at room tempera-
ture (r.t.), under an initial pressure of 50 psi. After the
absorption of the calculated amount of hydrogen, the
catalyst was removed by filtration and the solvent was
evaporated under reduced pressure. A total of 87%
yield of a white solid recrystallized from a mixture of
ethanol–water, m.p. 80–81°C (Lit. [10] 83°C). IR
(KBr, cm−1): 3400, 2000 (COOH), 1700 (CO). 1H
NMR (CDCl3): 0.68–2.00 (m, 6H, ArCH2CH2CH2,
ArCH2CH2CH2, CH2CH2COOH); 2.00–2.26 (m, 2H,
CH2COOH); 2.28–2.84 (m, 2H, ArCH2), 3.10–3.52 (m,
1H, ArCHꢀ), 6.51–7.89 (m, 4H, ArH), 9.73–10.15 (s,
1H, COOOH).
A solution of the previously synthesized pyridine
hydrobromide perbromide complex (3.42 g, 10.7
mmol), compound 8 (1.5 g, 8 mmol), in chloroform (50
ml) was heated. The temperature was kept at 50°C for
15 min. The mixture was poured over ice and benzene.
The organic phase was separated, washed several times
with water and then dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced
pressure, to obtain a brown crude, that was purified
using chromatographic column with silica gel 60
(0.040–0.060 mesh) and benzene as the eluant. 70%
1
Yield, m.p. 57–58°C. IR (KBr, cm−1): 1682 (CO). H
NMR (CDCl3): 0.63–2.21 (m, 6H, CH2CH2, CHCH2),
2.23–3.36 (m, 3H, ArCH2, ArCH), 4.42 (t, 1H,
COCHBr), 6.78–7.31 (m, 2H, ArH), 7.52–7.94 (m, 1H,
ArH).
3.1.4. 2,3,3a,4,5,6-Hexahydro-phenalen-1-one (8)
To polyphosphoric acid (24 g) heated previously to
60°C, compound 7 (2 g, 9.8 mmol) was added, and the
mixture was stirred manually for 30 min in an oil bath,
keeping the temperature between 90 and 120°C. Then,
crushed ice was added and the stirring produced precip-
itation of the product, which was extracted with
dichloromethane. The organic extracts were washed
with water, sodium bicarbonate, and water again and
then dried over anhydrous magnesium sulfate. The
solvent was removed under reduced pressure, to give a
yellow solid that recrystallized from a mixture of etha-
nol–water. 82% yield of a white solid. m.p. 68–69°C
(Lit. [10] 69.2–70°C). IR (KBr, cm−1): 3054 (ArH),
1676 (CO). 1H NMR (CDCl3): 0.52–2.21 (m, 6H,
ArCH2CH2CH2, ArCH2CH2CH2, ArCOCH2CH2),
2.23–3.19 (m, 5H, ArCOCH2, ArCH2, ArCH), 6.73–
7.36 (m, 2H, ArH), 7.52–7.94 (m, 1H, ArH).
3.1.7. 2-Azido-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-
one (10)
A solution of sodium azide (0.677 g, 10 mmol) in
water (5 ml) was added to a solution of compound 9
(1.38 g, 5.2 mmol) in DMF (20.8 ml) and acetic acid
(1.0 ml). The resulting mixture was kept at 5°C under
constant stirring. When the temperature reached 20°C,
the reaction was stopped after 1 h. Next, water was
added and the organic phase separated, washed several
times with water, and then dried over anhydrous mag-
nesium sulfate. The solvent was evaporated under re-
duced pressure and the obtained crude was purified
through chromatography column using silica gel 60
(0.040–0.060 mesh) using ethyl acetate as the eluant to
give purple oil. 84% Yield, rf 0.61 (ethyl acetate). IR
1
(film, cm−1): 2104 (N3), 1692 (CO). H NMR (CDCl3):
3.1.5. 3a,4,5,6-Tetrahydro-1H-phenalene-1,2(3H)-
dione-2-oxime (13)
0.52–2.42 (m, 4H, CH2CH2), 2.44–3.47 (m, 5H,
CH2CHN3, ArCH2, ArCH), 3.57–4.73 (m, 1H, CHN3),
7.0–7.52 (m, 2H, ArH), 7.73–8.36 (m, 1H, ArH).
C13H13N3O (227.26). Anal. Calc.: C, 68.71; H, 5.76; N,
18.49. Found: C, 69.03; H, 5.83; N, 18.49%.
A solution of compound 8 (1.68 g, 9 mmol), n-butyl
nitrite (1.57 g, 15.2 mmol) in t-butyl alcohol (20 ml)
was added to a solution of metallic sodium (0.34 g, 15.2
mmol) in t-butyl alcohol (20 ml). The resulting mixture
was stirred for 4 h at 50°C during the first hour, and at
r.t. the rest of the time. The solvent was evaporated at
reduced pressure and the resulting solid was dissolved
in water (25 ml). The aqueous solution was extracted
with benzene and then saturated with carbon dioxide,
producing the formation of a red semisolid residue that
3.1.8. Diasteromeric mixture of
2-amino-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-one
chlorhydrate (11)
A solution of compound 10 (0.72 g, 3.1 mmol) in
hydrochloric acid (2 ml), and ethanol (98 ml) was used
to perform a hydrogenation reaction over 10% Pd/C

J.E. Angel-Gu´ıo et al. / Il Farmaco 55 (2000) 575–582
579
(0.072 g) at r.t. under an initial pressure of 50 psi. After
absorption of the calculated amount of hydrogen, the
catalyst was removed by filtration and the solvent was
evaporated under reduced pressure to give an orange
solid that was recrystallized from a mixture of iso-
propanol–ether. 80% yield, m.p. 175°C (highly hygro-
scopic). IR (film, cm−1): 1655–1587 (NH+3 Cl−), 1682
(CO), 1281, 1260 (CꢀCOꢀC).
genated over 10% Pd–C (0.05 g) at r.t., under an initial
pressure of 50 psi. After absorption of the calculated
amount of hydrogen, the catalyst was removed by
filtration and the solvent evaporated under reduce pres-
sure. The residue was diluted with water, and made
basic to pH 10 with a sodium hydroxide (20%) solution,
then extracted with dichloromethane. The organic ex-
tracts were combined, dried over anhydrous magnesium
sulfate, and evaporated under reduced pressure. The
yellow oil obtained, was dissolved in chloroform and
treated with Et2O–HCl, to produce an amorphous
solid that was recrystallized from isopropanol–ether.
60% yield of a white solid, m.p. 202–203°C. IR (KBr,
3.1.9. Diasteromeric mixture of
2-amino-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-ol (12)
3.1.9.1. Route A. A solution of recently prepared com-
pound 11 (0,67 g, 2.8 mmol) in methanol (10 ml), was
added dropwise, to a suspension of sodium borohy-
dride (0.2137 g, 5.6 mmol) in methanol (10 ml). The
resulting mixture was kept at 5°C under constant stir-
ring for 1 h. The mixture was acidified with 2 N
hydrochloric acid and the solvent was evaporated under
reduced pressure; water (10 ml) was added and the
solution made basic using 2 N sodium hydroxide. The
mixture was extracted with chloroform, and the organic
phase washed with water several times; then dried over
anhydrous magnesium sulfate. The solvent was evapo-
rated under reduced pressure, to obtain a light brown
oil, which gave a solid after transformation with Et2O–
HCl in the corresponding chlorhydrate that was
purified by recrystallization from isopropanol–ether.
80% yield of a white solid, m.p. 205–206°C. IR (KBr,
1
cm−1): 2986, 1583 (NH3+Cl−). H NMR (DMSO-d6):
1.45 (m, 2H, CH2), 1.60 (m, 2H, CH2), 2.15 (m, 2H,
CH2), 2.25 (m, 2H, CH2), 2.52 (m, 1H, CH), 3.12 (m,
1H, CHNH+3 ), 3.35 (m, 2H, CH2), 6.28 (dd, 1H, ArH,
J1=8.03, J2=2.77 Hz), 6.40 (dd, 1H, ArH J1=8.03,
J2=2.77 Hz), 6.52 (m, 1H, ArH), 7.66 (bs, NH+3 Cl).
EM m/z: 187 (M−1, C13H16N, 2%); 186 (C13H15N,
11%); 170 (C13H14, 74%); 169 (C13H13, 100%); 144
(C11H12, 48%); 129 (C10H9, 79%); 115 (C9H7, 18%);
Anal. Calc.: C, 69.79; H, 8.11; N, 6.26. Found: C,
70.01; H, 8.12; N, 6.21%.
3.2. Pharmacology
Adult male Sprague-Dawley rats 250–300 g were
housed under controlled conditions of temperature and
light (light on from 06:00 to 18:00 h) and provided with
free access to laboratory chow and water. A cannula
was implanted in the left lateral ventricle of the rat,
under pentobarbital anesthesia (40 mg kg−1, i.p.). Sin-
gle intracerebroventricular (ICV) injection was made
with a Hamilton syringe fitted with a stopper to prevent
needle penetration past cannula tip. Three days after
ventricular cannulation the animals were randomly dis-
tributed into two groups. Animals were weighed and
placed in metabolic cages. At 09:00 half of the rats were
injected, as a bolus in 10 s, with saline solution (5 ml) or
with freshly prepared 2 in saline solution (50 mg/10 ml
and 100 mg/10 ml) followed by orally administration of
water (20 ml water/kg). Urine was collected at 3 and 6
h. The bladder was emptied after 6 h by gentle suprapu-
bic massage. Food and water were not available during
the experiment. Ventricular cannula placement was
confirmed postmortem by examining the distribution of
an ICV injection of 5 ml of a fast green dye, given
before the animals were killed. Data were used only if
the dye was distributed in the lateral, third and fourth
ventricles. Urine samples were assayed for sodium and
potassium concentrations by flame photometry. Statis-
tical differences between groups were analyzed using a
two-way analysis of variance and by the Newman–
Keul’s range statistics.
1
cm−1): 3367 (OH), 1520–1461 (NH+3 Cl−). H NMR
(DMSO-d6): 0.789–2.42 (m, 6H, CH2CH2, CHCH2),
2.63–3.84 (m, 4H, ArCH2, ArCH,CHNH+3 Cl−), 5.05
(d, 1H, J=9.47 Hz, ArCHOH), 7.21–8.1 (m, 4H,
+
−
+
’
(ArH)3, OH), (bs, 3H, NH3 Cl ). EM m/z: 239 (M
,
C13H18NOCl, 21%); 221 (C13H16NCl, 11%); 202
(C13H17NO, 20%); 185 (C13H15N, 20%); 175 (C12H17N,
17%); 160 (C11H12O, 14%); 145 (C10H9O, 18%); 130
(C10H10, 20%); 115 (C9H7, 16%); 91 (C7H7, 20%); 77
(C6H5, 16%). C13H17NO·HCl (239.74). Anal. Calc.: C,
65.13; H, 7.57; N, 5.84. Found: C, 64.88; H, 7.58; N,
5.84%.
3.1.9.2. Route B. A solution of compound 13 (0.4 g,
1.86 mmol) in hydrochloric acid (2 ml) and ethanol (98
ml) was used to perform a hydrogenation reaction over
10% Pd–C (0.04 g) at r.t. under an initial pressure of 50
psi. After absorption of the calculated amount of hy-
drogen, the catalyst was removed by filtration and the
solvent evaporated under reduced pressure to give a
white solids that was recrystallized from mixture of
isopropanol–ether.79% yield, m.p. 205–206°C.
3.1.10. Diasteromeric mixture of 2-amine
2,3,3a,4,5,6-hexahydro-1H-phenalen chlorhydrate (2)
A solution of compound 12 (0.5 g, 2 mmol) in acetic
acid (90 ml) and sulfuric acid (10 ml), was hydro-

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J.E. Angel-Gu´ıo et al. / Il Farmaco 55 (2000) 575–582
Fig. 2. Urinary responses to ICV administration of compound 2 in rats. A group of rats were ICV treated with compound 2 at doses of 50 or
100 ml/10 ml; control rats received ICV saline (10 ml). The results revealed a significant decrease (x) of urinary sodium and potassium excretion
after 3 and 6 h (50 ml/100 ml) (P*B001).
3.3. Computational method
sults demonstrated that central administration of
compound 2, not only did not show the diuretic and
natriuretic effects, but on the contrary, compound 2
induced a dose dependent reduction in urinary sodium
and potassium excretion (Fig. 2 and Table 1). The exact
mechanisms by which central administration of com-
pound 2 gives rise to an antinatriuretic and antikali-
uretic effect are unknown.
Computational calculation was performed using the
Hartree–Fock AM1 method [16]. The computational
program used for optimizations was AMPAC
UNIX) and the display was carried out with the pro-
grams DMM [17] and PLUTO [18].
(SUN-
It was reported in the synthesis and pharmacological
evaluation of several tricyclic amines that compound 3
showed dopaminergic activity through the stimulation
of the dopamine D-2 receptor [9]. In this respect we
could point out that the basic nucleus of compound 2 is
4. Results and discussion
Compound 2, like compound 1, is considered a rigid
non-hydroxylated 2-amino indane, which also presents
the partial moiety of the phenylethylamine pharma-
cophore. Despite the fact that compound 1 possesses
one carbon atom less on its skeleton than compound 2,
we hypothesized that it should show a similar biological
activity as the one described previously for compound
1. In effect, we have shown that central administration
of dopamine and compound 1 induces diuresis and
natriuresis [7,19]. The involvement of the brain do-
paminergic system in the centrally mediated renal ac-
tion of compound 1 was strongly supported by the fact
that the natriuretic and diuretic response was inhibited
by haloperidol and when the endogenous dopamine
levels were reduced after selective dopamine denerva-
tion [6,7]. However and unexpectedly, our present re-
Table 1
Effect of compound 2 on electrolyte urinary excretion a
Urinary
Dose administrated
Inhibition (%)
excretion
(mg)
3 h
6 h
Sodium
Sodium
Potassium
Potassium
50
100
50
52
14
43
31
36
27
33
23
100
a Results are expressed as percentage on inhibition compared with
the basal excretion.

J.E. Angel-Gu´ıo et al. / Il Farmaco 55 (2000) 575–582
581
that they influence a common output system, but in
opposite directions: D-1 receptor induced hyperthermia
and stimulation of D-2 receptor, hypothermia [22].
Future studies are carried out to confirm our hypoth-
esis and to suggest which stereoisomer of diasteromeric
mixture is responsible for that particular activity.
Acknowledgements
We are indebted to CONICIT-Venezuela, Grant No
S1 97000394 and LAB 97000665. The computer time
Grant is grateful to CECALCULA National Center of
Scientific Computation of the University of Los Andes.
Fig. 3. Overlapping of the nuclei of compounds 2 and 3 using AM1
semiempirical method. Compound 3 possesses the nitrogen atom at
position 4. Shrinking of the molecular area is observed.
References
an isoster of compound 3; differing only at the nitrogen
atom at position 4 in the benzo-[ij ]-quinolizine system.
Furthermore, compound 2 is a primary amine, while
compound 3 is a dipropylated tertiary amine. Thus,
apparently, these two compounds should have the same
area. As a consequence of this fact, we could postulate
that the nitrogen atom at position 4 in compound 3
would modify the base nucleus geometry, shrinking the
area. This result was confirmed through a theoretical
study using the AM1 method [16] when comparing
both compounds as primary amines. In this work, the
geometry of 2 and 3 was calculated and the results are
summarized in Fig. 3. We can observe how the substi-
tution of a carbon atom for nitrogen caused the men-
tioned shrinking of area.
Taking into consideration these findings, we could
speculate that compound 2 occupancy of the D-2 recep-
tor with no intrinsic activity induces a dopaminergic
antagonism on urinary sodium and potassium excre-
tion. Furthermore, the inhibition of urinary electrolyte
excretion observed in the present results may indicate
that the blockade of the brain dopaminergic receptor
by compound 2 inhibits the tonic endogenous do-
pamine regulation of sodium and potassium balance.
Consequentially, stimulation of the D-1 receptor would
result in a reduction in urinary sodium and potassium
excretion. In this respect, there is evidence of opposi-
tional D-1:D-2 interactions which appears to constitute
another general mode of dopaminergic regulation. In-
deed, while tonic activity, through D-1 receptor is
necessary for the expression of typical D-2 stimulated
behavior, via the well-known cooperative/synergic D-
1:D-2 interactions [20], D-1 tone normally inhibits via
oppositional D-1:D-2 interactions, the expression of
atypical D-2 — stimulated behaviors such as jerking
[21]. Furthermore, It has been shown that D-1:D-2
receptors act differentially on body temperature, and
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