Structural determinants for high 5-HT2A receptor affinity of spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine (SpAMDA)

Article abstract of DOI:10.1016/j.bmcl.2004.02.014

The synthesis and 5-HT_2A receptor affinities of ring altered derivatives of spiro[9,10-dihydroanthracene]-9,3^′-pyrrolidine (4), a structurally unique tetracyclic 5-HT_2A receptor antagonist, are described. The characteristi

Full text of DOI:10.1016/j.bmcl.2004.02.014

Bioorganic & Medicinal Chemistry Letters 14 (2004) 2279–2283
Structural determinants for high 5-HT2A receptor affinity of
spiro[9,10-dihydroanthracene]-9,30-pyrrolidine (SpAMDA)
Srinivas Peddi,a Bryan L. Roth,b Richard A. Glennona and Richard B. Westkaempera,*
aDepartment of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, PO Box 980540,
Richmond, VA 23298, USA
bNIMH Psychoactive Drug Screening Program and Departments of Biochemistry and Psychiatry, Case Western Reserve University
School of Medicine, Cleveland, OH 44106, USA
Received 18 July 2003; accepted 2 February 2004
Abstract—The synthesis and 5-HT2A receptor affinities of ring altered derivatives of spiro[9,10-dihydroanthracene]-9,30-pyrrolidine
(4), a structurally unique tetracyclic 5-HT2A receptor antagonist, are described. The characteristics of the parent compound prove to
be necessary for optimal 5-HT2A receptor affinity. However, expansion of the size of the pyrrolidine and central rings produce
compounds with reasonably high 5-HT2A receptor affinities. In addition, the parent compound is shown to have high 5-HT2 receptor
selectivity.
ꢀ 2004 Elsevier Ltd. All rights reserved.
We have previously found that the phenylethylamine-
containing tricyclic compound 1-(aminomethyl)-9,10-
dihydroanthracene (AMDA, 1, Fig. 1) is a selective,
high affinity 5-HT2 antagonist.1–5 In the course of
investigating the structure–affinity relationships for
derivatives based on the AMDA skeleton, we demon-
strated that both 9-methylation and N-methylation (2,
3, Fig. 1) decrease affinity only slightly. We have
recently found that the tetracyclic compound spiro[9,10-
dihydro-anthracene]-9,30-pyrrolidine (SpAMDA, 4, Fig.
1) conceptually derived by homologation and cycliza-
tion of either 2 or 3, is a high affinity 5-HT2A antago-
nist.6 It has been demonstrated that both aromatic rings
of AMDA are necessary for optimal activity and that
compounds with the highest affinity have a symmetrical
fold between the aromatic moieties. The aminoalkyl side
chain of AMDA most likely adopts an axial configura-
tion with two energetically accessible side chain rotom-
ers, one folded (endo) and the other extended (exo).4
Receptor modeling, ligand structure–affinity relation-
ships, and site-directed mutagenesis studies suggest that
AMDA and AMDA derivatives bind 5-HT2A receptors
at a site that may be overlapping with but is distinct
from the site for typical 5-HT2A receptor antagonists.5
As demonstrated for AMDA, SpAMDA does not con-
NH2
NH2
NHCH3
1, 20 nM
3, 52 nM
2, 65 nM
NH
NH
NH
5, >10,000 nM
4, 4 nM
6, >10,000 nM
NH
NH
NH
7, 4610 nM
8, 110 nM
9, 99 nM
Figure 1. Structures and receptor affinities of compounds 1–9 at
[3H]ketanserin-labeled cloned 5-HT2A sites. Values represent the mean
of computer-derived Ki estimates (using LIGAND) of quadruplicate
determinations. Standard errors typically range between 15 and 25% of
the Ki values. The Ki values for compounds 1–4 were previously
reported (Refs. 3, 4, and 6).
form to existing pharmacophore models for 5-HT2A
receptor antagonists.6 SpAMDA can exist as any of four
energetically equivalent minima, all of which resemble
the exo form of AMDA more closely than the endo
form.6 Although AMDA (1) and SpAMDA (4) share a
* Corresponding author. Tel.: +1-804-828-6449; fax: +1-804-828-7625;
e-mail: richard.westkaemper@vcu.edu
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.02.014

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S. Peddi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2279–2283
common tricyclic amine fragment, it was necessary to
evaluate the dependence of receptor affinity on struc-
tural features common to the tricyclic AMDA and the
tetracyclic SpAMDA compounds before optimization
of SpAMDA like compounds could be carried out in
a rational way.
1. Ligand synthesis
9,10-Dihydroanthracene-9-carboxamide7 (4a) on treat-
ment with POCl3 gave 9-cyano-9,10-dihydro anthracene
(4b), which was alkylated using C2H5OCOCH2Br in
presence of C2H5ONa/C2H5OH to give (9-cyano-9,10-
dihydroanthracen-9-yl)-acetic acid ethyl ester (4c). The
ester 4c was then subjected to reductive cyclization
using 10% Pd/C in presence of HCl in CH3OH to give
spiro[9,10-dihydroanthracene]-9,40-pyrrolidin-20-one (4d),
which was further reduced to spiro[9,10-dihydroanthra-
cene]-9,30-pyrrolidine (4) using BH3–THF complex
(Scheme 1).
The fact that 5 has no measurable affinity for 5-HT2A
receptors (5; Ki > 10; 000 nM) suggests that the phenyl-
pyrrolidine fragment of SpAMDA is not sufficient for
binding. Removing one aromatic ring from SpAMDA
(4; Ki ¼ 4 nM) drastically reduces affinity as indicated
by the tetrahydronaphthalene 6 (Ki > 10,000 nM). This
suggests that the enhanced affinity of SpAMDA (4) over
phenylethylamine (Ki ¼ 16,800 nM), and the phenyl-
pyrrolidine is not due solely to the presence of the cen-
tral ring. The simple presence of two aromatic rings is
also not sufficient for optimal affinity as demonstrated
3-Phenyl pyrrolidine (5) was synthesized starting from
phenyl-succinonitrile according to a literature method.8
Spiro[1,2,3,4-tetrahydronaphthalenyl)-1,30-pyrrolidine
(6), 3,3-diphenylpyrrolidine (7), and spiro(10,11-dihy-
dro-dibenzo[a,d]cycloheptene)-5,30-pyrrolidine (8), were
synthesized by the method adopted for 4 starting from
1-cyano-1,2,3,4-tetrahydronaphthalene,9 diphenyl ace-
tonitrile, and 5-cyano-10,11-dihydrodibenzo[a,d]-cyclo-
heptene10, respectively. Spiro[9,10-dihydroanthra-cene]-
9,30-piperidine (9) was synthesized from 4b using
C2H5OCO(CH2)2Br as the alkylating agent.
by compound 7. The 3,3-diphenyl-pyrrolidine
7
(Ki ¼ 4610 nM), while enhanced in affinity compared to
phenylethylamine, has 1200-fold lower affinity than
SpAMDA (4). The [a,d]dibenz-fused cycloheptane 8
(Ki ¼ 110 nM) has a lower affinity than SpAMDA (4)
but binds reasonably well suggesting that with Sp-
AMDA, as has been demonstrated with AMDA, com-
pounds with a substantial symmetrical aromatic fold can
bind to the receptor with high affinity. Expansion of the
spiropyrrolidine of SpAMDA to a spiropiperidine 9
results in a modest decrease in affinity (25-fold). Thus, it
appears that both the presence and orientation of two
aromatic rings in a tricyclic configuration, and a basic
amine constrained within a spiropyrrolidine system, are
necessary for optimal affinity. Although there is a
superficial similarity between SpAMDA and classical
tricyclic antidepressants, the lack of a common phar-
macophore between AMDA and SpAMDA and classi-
cal agents suggests that SpAMDA may bind to 5-HT2A
receptors in a different manner. The difference between
SpAMDA and other tricyclic agents is further supported
by selectivity data (Table 1). Given the high degree of
receptor sequence homology between the 5-HT2A and
5-HT2C receptors, it is not surprising that SpAMDA
shows little selectivity (6-fold) between the subtypes.
SpAMDA is, however, remarkably selective for 5-HT2A
receptors versus dopamine D2 receptors and serotonin
(SERT) and norepinephrine (NET) transporters, sites
at which many tricyclic antidepressants bind.
1.1. 9-Cyano-9,10-dihydroanthracene (4b)
POCl3 (5.5 mL, 59 mmol) was added to crystalline 9,10-
dihydroanthracene carboxamide (0.54 g, 2.43 mmol)
O
O
O
NH2
CN
CN
(a)
(b)
O
4b
4a
4c
NH
NH
(c)
(d)
4
4d
Scheme 1. (a) POCl3, NH4OH (b) EtOCOCH2Br, EtONa/EtOH;
EtOCOCH2CH2Br, EtONa/EtOH for (9) (c) 10% Pd/C, H2, MeOH,
HCl (d) BH3–THF, 6.0 M HCl.
Table 1. Receptor and transporter selectivities of SpAMDA (4) and classical tricyclic agents
Compound
Ki, nM
SERTd
NETe
a
b
c
5-HT2A
5-HT2C
D2
SpAMDA (4)
imipramine
cyproheptadine
4
94
3
24
160
11
5,000
726
112
3,900
5
4100
10,000
16
290
a [3H]ketanserin.
b [3H]mesulergine.
c [3H]spiperone.
d [3H]paroxitine.
e [3H]nisoxitine radioligands.

S. Peddi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2279–2283
2281
with stirring. The solution was then heated at reflux
(45 min) and poured into a mixture of crushed ice/
NH4OH with vigorous stirring (15 min). Excess of
NH4OH was added to keep the solution alkaline. The
solid formed was extracted with Et2O (3 · 50 mL). The
combined Et2O extracts were washed with water, brine,
dried (MgSO4), and removal of Et2O under reduced
pressure gave a yellow oil, which crystallized immedi-
ately. The product was purified by MPLC using hex-
anes/EtOAc (9:1) as eluent to give 0.3 g (60%) of pure
9-cyano-9,10-dihydro-anthracene as colorless crystals
2.1.3. 3-Cyano-3,3-diphenyl-propionic acid ethyl ester.
1
Yield (75%); mp 99–10 ꢁC (EtOAc/petroleum ether). H
NMR (CDCl3) d 1.08–1.13 (t, J ¼ 7:5 Hz, 3H, CH3),
3.41 (s, 2H, CH2), 4.03–4.10 (q, J ¼ 15 Hz, 2H, CH2),
7.21–7.39 (m, 10H, Ar-H); 13C NMR (CDCl3) d 14.45,
44.73, 48.97, 61.76, 127.31, 128.76, 129.54, 139.78,
168.71.
2.1.4. 5-(Cyano-10,11-dihydrodibenzo[a,d]cycloheptene-5-
yl)-acetic acid ethyl ester. Yield (55%); colorless oil. H
1
1
mp 106–108 ꢁC. lit.11 mp 101–102 ꢁC. IR cmꢀ1 2215. H
NMR (CDCl3) d 1.01–1.06 (t, J ¼ 7:5 Hz, 3H, CH3),
3.04–3.47 (m, 4H, CH2), 3.50 (s, 2H, CH2), 3.91–3.98 (q,
J ¼ 13:5 Hz, 2H, CH2), 7.13–8.07 (m, 8H, Ar-H); 13C
NMR (CDCl3) d 14.39, 34.21, 48.21, 52.36, 61.59,
122.42, 127.34, 129.27, 129.54, 132.17, 135.29, 139.46,
168.23.
NMR (CDCl3) d 3.87–3.93 (d, J ¼ 18 Hz, 1H, CH2),
4.05–4.11 (d, J ¼ 18 Hz, 1H, CH2), 5.02 (s, 1H, CH),
7.28–7.79 (m, 8H, Ar-H); 13C NMR (CDCl3) d 36.14,
37.60, 119.54, 125.88, 127.12, 127.60, 128.53, 128.82,
129.56, 131.34, 136.65.
2.1.5. 3-(9-Cyano-9,10-dihydroanthracen-9-yl)-propionic
acid ethyl ester. Yield (82%); colorless oil. 1H NMR
(CDCl3) d 1.15–1.20 (t, J ¼ 7:5 Hz, 3H, CH3), 2.20–2.44
(m, 4H, CH2), 3.94–4.16 (m, 4H, CH2), 7.32–7.79 (m,
8H, Ar-H); 13C NMR (CDCl3) d 14.67, 31.27, 35.20,
37.36, 48.77, 61.24, 121.78, 127.26, 127.66, 128.75,
129.05, 134.57, 135.01, 172.30.
2. Methods for the synthesis of spiro-pyrrolidines
(4, 6–9)
2.1. General method for the synthesis of the cyano acetic
acid ethyl esters
Nitrile (6.09 mmol) was added to sodium ethoxide pre-
pared from Na (8.53 mmol) and EtOH (10 mL) and
heated at reflux (1 h). The solution was then cooled in
an ice bath and C2H5OCOCH2Br (8.53 mmol) or
C2H5OCO(CH2)2Br (8.53 mmol) was added dropwise
via a syringe. The resulting mixture was heated at reflux
(4 h) cooled and filtered. The residue was washed with
Et2O (25 mL). Water (25 mL) was added to the filterate
and the organic layer was separated. The aqueous layer
was once again extracted with ether (25 mL). The com-
bined Et2O extracts were washed with water, brine,
dried (MgSO4), and evaporated under reduced pressure
to give an oil, which was purified by MPLC using hex-
anes/EtOAc (9:1) as eluent to give the respective cyano
acetic or propionic acid ethyl esters.
2.2. General method for the synthesis of spiro-pyrrolidin-
20-ones
A mixture of the cyanoester (2.06 mol), 10% Pd/C
(0.15 g) in methanol (40 mL), and HCl (1 mL) was
hydrogenated at 50 kg/cm3 (3 days). The catalyst was
removed and the solvent was evaporated under reduced
pressure to give a white semisolid. Water (25 mL) was
added and the solution was made basic with 10% NaOH
and extracted with EtOAc (3 · 25 mL). The combined
EtOAc extracts were washed with water, brine, dried
(MgSO4), and evaporated under reduced pressure to
give a yellow oil. The oil was purified by mplc using
hexane/EtOAc (9:1) as eluent to give the respective
spiro-pyrrolidin-20-ones.
2.1.1. (9-Cyano-9,10-dihydroanthracen-9-yl)-acetic acid
ethyl ester (4c). Yield (70%); mp 69–70 ꢁC (EtOAc/
petroleum ether). 1H NMR (CDCl3) d 1.10–1.15 (t,
J ¼ 7:5 Hz, CH3), 2.85 (s, 2H, CH2), 3.97–4.14 (m, 4H,
CH2), 7.33–7.89 (m, 8H, Ar-H); 13C NMR (CDCl3) d
14.53, 35.27, 46.05, 46.28, 61.63, 121.89, 127.58, 127.70,
128.93, 134.21, 135.10, 167.96.
2.2.1. Spiro[9,10-dihydroanthracene]-9,40-pyrrolidin-20-
one (4d). Yield (68%); mp 189–190 ꢁC (CHCl3/petro-
leum ether). 1H NMR (CDCl3) d 3.06 (s, 2H, CH2), 3.70
(s, 2H, CH2), 4.00–4.06 (d, J ¼ 18 Hz, 1H, CH2), 4.09–
4.15 (d, J ¼ 18 Hz, 1H, CH2), 6.15 (s, 1H, NH), 7.24–
7.58 (m, 8H, Ar-H); 13C NMR (CDCl3) d 36.37, 43.20,
47.49, 55.66, 125.04, 127.50, 128.73, 136.35, 141.36,
178.40.
2.1.2. (1-Cyano-1,2,3,4-tetrahydronaphthalen-1-yl)-acetic
acid ethyl ester. Yield (61%); golden yellow oil. 1H NMR
(CDCl3) d 1.20–1.26 (t, J ¼ 9 Hz, 3H, CH3), 1.89–1.97,
(m, 2H, CH2), 2.28–2.32 (t, J ¼ 6 Hz, 2H, CH2), 2.79–
3.06 (m, 4H, CH2), 4.11–4.20 (q, 2H, CH2), 7.10–7.47
(m, 4H, Ar-H); 13C NMR (CDCl3) d 14.65, 19.46, 29.44,
33.20, 38.18, 44.82, 61.61, 123.78, 127.39, 128.24,
128.72, 130.51, 134.48, 136.85, 169.20.
2.2.2. Spiro[1,2,3,4-tetrahydronaphthalenyl)-1,40-pyrrol-
idin-2-one. Yield (70%); mp 152–153.5 ꢁC (CHCl3/
petroleum ether) lit. mp 148–158 ꢁC12. 1H NMR
(CDCl3) d 1.77–2.03 (m, 4H, CH2), 2.44–2.73 (m, 2H,
CH2), 2.79–2.83 (t, J ¼ 6 Hz, 2H, CH2), 3.43–3.46 (d,
J ¼ 9 Hz, 1H, CH2), 3.61–3.64 (d, J ¼ 9 Hz, 1H, CH2),
7.06–7.38 (m, 4H, Ar-H), 7.56 (s, 1H, NH); 13C NMR

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S. Peddi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2279–2283
1
(CDCl3) d 20.64, 30.60, 37.72, 42.39, 48.06, 57.97,
126.93, 127.22, 129.90, 137.22, 142.38, 178.51.
CH3OH). H NMR (CDCl3) d 1.71–2.27 (m, 6H, CH2),
2.72 (s, 2H, CH2), 3.30–3.50 (m, 4H, CH2), 7.06–7.47
(m, 4H, Ar-H); 13C NMR (CDCl3) d 20.00, 29.89,
34.20, 44.54, 45.35, 57.56, 126.71, 126.79, 127.05,
129.51, 137.99, 139.26, 164.93. Anal. Calcd for
(C13H17N.C2H2O4): C, 64.96; H, 6.90; N, 5.05. Found:
C, 64.99; H, 6.93; N, 4.96.
2.2.3. 4,4-Diphenylpyrrolidin-2-one. Yield (75%); mp
160–161 ꢁC (CHCl3/petroleum ether). 1H NMR (CDCl3)
d 3.04–3.05 (d, J ¼ 3 Hz, 2H, CH2), 4.01–4.03 (d,
J ¼ 6 Hz, 2H, CH2), 6.92 (br s, 1H, NH), 7.18–7.34 (m,
10H, Ar-H); 13C NMR (CDCl3) d 44.69, 51.64, 54.54,
127.20, 127.35, 129.21, 146.64, 177.46.
2.3.3. 3,3-Diphenylpyrrolidine oxalate (7). Yield (91%);
mp 184–185 ꢁC (EtOAc/CH3OH). 1H NMR (DMSO-d6)
2.2.4. Spiro[10,11-dihydrodibenzo[a,d]cycloheptene-5,40-
pyrrolidin]-20-one. Yield (55%); mp 198–199 ꢁC (CHCl3/
petroleum ether). lit. mp 201–202 ꢁC.7 1H NMR
(CDCl3) d 3.18–3.48 (m, 6H, CH2), 4.15 (s, 2H, CH2),
7.08–7.31 (m, 8H, Ar-H); 13C NMR (CDCl3) d 32.80,
40.44, 44.37, 55.24, 93.06, 125.28, 125.71, 126.79,
127.224, 127.98, 128.29, 129.93, 131.98, 138.88, 142.92,
177.37.
d
2.68–2.72 (t, J ¼ 6 Hz, 2H, CH2), 3.13–3.17(t,
J ¼ 6 Hz, 2H, CH2), 3.92 (s, 2H, CH2), 7.18–7.43 (m,
10H, Ar-H); 13C NMR (DMSO-d6) d 35.98, 43.72,
53.18, 54.86, 126.90, 127.07, 128.99, 144.48, 165.37.
Anal. Calcd for (C16H17N.C2H2O4): C, 68.99; H, 6.11;
N, 4.46. Found: C, 69.07; H, 6.13; N, 4.53.
2.3.4. Spiro(10,11-dihydrodibenzo[a,d]cycloheptene)-5,30-
pyrrolidine fumarate (8). Yield (77%); mp 169–170 ꢁC
Spiro[9,10-dihydroanthracene]-9,50-piperidin-20-
1
2.2.5.
(EtOAc/CH3OH). H NMR(DMSO-d6) d 2.70–2.75 (t,
one. Yield (66%); mp 189–190 ꢁC. (CHCl3/petroleum
J ¼ 7:5 Hz, 2H, CH2), 3.14–3.19 (t, J ¼ 7:5 Hz, 2H,
CH2), 3.29–3.37 (m, 4H, CH2), 3.73 (s, 2H, CH2), 7.07–
7.29 (m, 8H, Ar-H); 13C NMR (DMSO-d6) d 32.74,
38.25, 45.76, 58.14, 125.66, 126.54, 127.35, 131.98,
138.79, 144.67. Anal Calcd for (C19H21N.C4H4O4.1/
4H2O): C, 71.42; H, 6.40; N, 3.78. Found: C, 71.35; H,
6.61; N, 3.65.
1
ether). H NMR (CDCl3) d 2.04–2.18 (m, 4H, CH2),
3.93–4.25 (m, 4H, CH2), 7.31–7.61 (m, 8H, Ar-H); 13C
NMR (CDCl3) d 30.25, 31.36, 37.32, 41.22, 49.16,
124.89, 127.33, 129.04, 137.34, 141.36, 172.60.
2.3. General method for the reduction of the spiropyrrol-
idin-2-ones to spiro pyrrolidines
2.3.5. Spiro[9,10-dihydroanthracene]-9,30-piperidine oxal-
ate (9). Yield (77%); mp 193–194 ꢁC (EtOAc/CH3OH).
1H NMR (CDCl3) d 1.72–1.81 (t, J ¼ 3 Hz, 2H, CH2),
2.09–2.18 (m, 2H, CH2), 2.94–2.98 (m, 2H, CH2), 3.45
(s, 2H, CH2), 4.00–4.06 (d, J ¼ 18 Hz, 1H, CH2), 4.10–
4.16 (d, J ¼ 18 Hz, 1H, CH2), 7.19–7.89 (m, 8H, Ar-H);
13C NMR (CDCl3) d 24.79, 33.45, 38.07, 42.18, 47.60,
54.09, 126.23, 123.32, 123.61, 128.69, 138.18, 144.57.
Anal. Calcd for (C18H19N.C2H2O4): C, 70.77; H, 6.23;
N, 4.12. Found: C, 70.93; H, 6.19; N, 4.05.
A 1.0 M solution of BH3–THF complex (7.00 mol) was
added at 0 ꢁC to a well stirred solution of 4-spiro-pyr-
rolidin-2-ones (1.40 mmol) in anhydrous THF (2 mL).
The solution was brought to room temperature and then
heated at reflux (8 h) and cooled. HCl (4 mL) of 6.0 M
solution was added cautiously to the reaction mixture,
heated at reflux (1 h), cooled, and the solvent was
removed under reduced pressure, resulting in a white
suspension. Water (20 mL) was added and extracted
with EtOAc (20 mL). The aqueous phase was made
basic with 10% NaOH and extracted with CH2Cl2
(3 · 25 mL). The combined CH2Cl2 extracts were washed
with water, brine, dried (MgSO4), and the solvent was
removed under reduced pressure to give the respective
amines as oils.
2.3.6. Affinity determinations. Radioligand binding
assays using [3H]-ketanserin and cloned 5HT2A recep-
tors were performed as previously described. Data were
analyzed with the LIGAND program as previously
detailed.13;14
2.3.1. Spiro[9,10-dihydroanthracene]-9,30-pyrrolidine fum-
arate (4). Yield (94%); mp 190.5–191.5 ꢁC (EtOAc/
Acknowledgements
CH3OH). 1H NMR (DMSO-d6)
d 2.25–2.30 (t,
J ¼ 7:5 Hz, 2H, CH2), 3.21–3.26 (t, J ¼ 7:5 Hz, 2H,
CH2), 3.55 (s, 2H, CH2), 4.06 (s, 2H, CH2), 6.44 (s, 1H),
7.20–7.56 (m, 8H, Ar-H); 13C NMR (DMSO-d6) d 36.22,
36.67, 45.18, 51.09, 54.10, 124.43, 126.69, 126.76,
128.17, 135.84, 137.08, 141.44, 168.96. Anal. Calcd for
(C17H17N.1/2C4H4O4): C, 77.79; H, 6.52; N, 4.77.
Found: C, 77.12; H, 6.56; N, 4.78.
This was supported by United States Public Health
Service Grant MH57969 (R.B.W.) and the NIMH Psy-
choactive Drug Screening Program NO280005 (B.L.R.).
References and notes
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Savage, J. E.; Roth, B. L.; Glennon, R. A. Eur. J.
Pharmacol. 1999, 380, R5.
2.3.2. Spiro[1,2,3,4-tetrahydronaphthalenyl)-1,30-pyrrol-
idine oxalate (6). Yield (80%); mp 197–198 ꢁC (EtOAc/

S. Peddi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2279–2283
2283
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