8-[4-[2-(1,2,3,4-Tetrahydroisoquinolinyl)]butyl]-8-azaspiro[4.5]decane- 7,9-dione: A new 5-HT(1A) receptor ligand with the same activity profile as buspirone

Article abstract of DOI:10.1021/jm950662c

A new analog of buspirone (1), i.e., 8-[4-[2-(1,2,3,4- tetrahydroisoquinolinyl)]butyl]-8-azaspiro-[4.5]decane-7,9-dione (6a), was synthesized. In was demonstrated that buspirone and its analog 6a were equipotent 5-HT(1A) ligands. Several behavioral models showed that 6a had essentially the same functional profile at 5-HT(1A) receptors as buspirone. The obtained results permit a conclusion that the basic nitrogen atom and terminal, bulky cycloimide moiety, but not the 2-pyrimidinyl group, of buspirone are directly involved in the formation of the bioactive complex with 5-HT(1A) receptors.

Full text of DOI:10.1021/jm950662c

J . Med. Chem. 1996, 39, 1125-1129
1125
8-[4-[2-(1,2,3,4-Tetr a h yd r oisoqu in olin yl)]bu tyl]-8-a za sp ir o[4.5]d eca n e-7,9-d ion e:
A New 5-HT1A Recep tor Liga n d w ith th e Sa m e Activity P r ofile a s Bu sp ir on e†
J erzy L. Mokrosz,* Anna Deren´-Wesołek,‡ Ewa Tatarczyn´ska,‡ Beata Duszyn´ska, Andrzej J . Bojarski,
Maria J . Mokrosz, and Ewa Chojnacka-Wo´jcik‡
Departments of Medicinal Chemistry and New Drugs, Institute of Pharmacology, Polish Academy of Sciences,
12 Sme¸tna Street, 31-343 Krako´w, Poland
Received September 6, 1995X
A new analog of buspirone (1), i.e., 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]butyl]-8-azaspiro-
[4.5]decane-7,9-dione (6a ), was synthesized. In was demonstrated that buspirone and its analog
6a were equipotent 5-HT1A ligands. Several behavioral models showed that 6a had essentially
the same functional profile at 5-HT1A receptors as buspirone. The obtained results permit a
conclusion that the basic nitrogen atom and terminal, bulky cycloimide moiety, but not the
2-pyrimidinyl group, of buspirone are directly involved in the formation of the bioactive complex
with 5-HT1A receptors.
In tr od u ction
compound in the structure-affinity relationship studies
of some 5-HT1A ligands.22,23 Its ionization constant at
37 °C (pKa ) 9.30)24 is similar to those reported for
simple 1-arylpiperazines (pKa ) 7.94-9.14),25 but sig-
nificantly lower than that of piperidine (pKa ) 10.86).24
The lipophilicity of THIQ is also comparable with that
of many 1-arylpiperazines but higher than that of
1-PP.24,25 The crucial distance between the aromatic
ring center and the basic nitrogen atom in THIQ (dArN
) 3.77 Å) is too short to form a bioactive complex of
THIQ with 5-HT1A receptors.22 As a result, THIQ (9)
shows no affinity for these receptors (Ki > 50 000 nM,
Table 1). Hence the THIQ nitrogen atom may mimic
the basic N-4 atom of 1-arylpiperazine at the 5-HT1A
receptors.23 In order to have a better insight into the
interaction modes of buspirone (1; a postsynaptic partial
agonist)1,2 and compounds 2-4 (postsynaptic antago-
nists)16,26,27 with 5-HT1A receptors, we modified their
structures by replacing 1-arylpiperazine fragments with
THIQ. If one can assume that the buspirone molecule
(or other ligand of this type) is recognized by the 5-HT1A
receptor in the manner discussed above,14,17-19 the
applied modification should directly result in a substan-
tial decrease of the receptor affinity.
Up to the present, buspirone (1) is the only second-
generation anxiolytic used in therapy. Its pharma-
cological1-9 and receptor binding profiles9-12 have been
well established. Buspirone is classified as a partial
agonist of 5-HT1A receptors; moreover, it is believed that
such a functional profile is responsible for its anxiolytic
activity. Buspirone may be regarded as a classic 5-HT1A
ligand with a relatively high affinity (Ki ) 9.3-29.5
nM).9-13 The interaction modes of buspirone and the
related compounds with the 5-HT1A receptors, as well
as the structure-affinity relationships of long-chain
arylpiperazines, have been discussed in a number of
papers. Fortunately, the latter issue was extensively
reviewed by Glennon et al.,14-16 who formulated some
general structure-affinity relationships for the long-
chain arylpiperazines of type 1. The latter authors
concluded that a wide range of 1-aryl substituents of
piperazine were tolerated at the receptor and that the
piperazine ring seemed to be optimal. Other important
features of the buspirone-type 5-HT1A ligands are
terminal amide or cyclic imide fragments and a spacer
that separates these fragments from the N-4 piperazine
atom.16 Moreover, it is generally accepted that the
buspirone molecule is recognized by the 5-HT1A receptor
due to the presence of 1-(2-pyrimidinyl)piperazine (1-
PP).14,17-19 In other words, the 1-PP fragment of 1
fulfills the minimal structure requirements defined by
Hibert et al.18,19 for the interaction with the 5-HT1A
binding site, one being the presence of an aromatic ring
and the other the presence of a basic nitrogen atom at
a distance of 5.2-5.7 Å from the center of the aromatic
system. On the other hand, the terminal imide moiety
offers an additional site of interaction with the 5-HT1A
receptor, which results in a greatly enhanced affinity
of buspirone in relation to 1-PP (Ki ) 1410 nM),14,17-19
though the nature of this interaction is so far only
speculative.13,14,18,20,21
Ch em istr y
A commercial N-(ω-bromoalkyl)phthalimide (7 or 8)
was treated with 1,2,3,4-tetrahydroisoquinoline (9) to
yield an imide derivative (5b or 6b). Hydrazinolysis of
5b and 6b afforded N-(ω-aminoalkyl)-1,2,3,4-tetrahy-
droisoquinolines 10 and 11 which, by acylation with 12,
were converted to 5a and 6a , respectively (Scheme 1).
Compound 6c was obtained by a simple two-step
condensation as shown in Scheme 2.
P h a r m a cology
The affinity of compounds 1, 2, 5, and 6 for 5-HT1A
receptors of the rat brain hippocampus was assessed on
the basis of their ability to displace [3H]-8-OH-DPAT
(Table 1). In order to show behavioral effects of bu-
spirone (1) and its analog 6a , which are mediated by
postsynaptic 5-HT1A receptors, the following in vivo
models were employed, induction of the lower lip retrac-
tion (LLR) in rats,6,28,29 induction of the behavioral
syndrome (flat body posture and forepaw treading), and
Our previous papers showed that 1,2,3,4-tetrahydro-
isoquinoline (THIQ, 9) may be regarded as a model
† Part 28 of the series: Structure-Activity Relationship Studies of
CNS Agents.
‡ Department of New Drugs.
X Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
0022-2623/96/1839-1125$12.00/0 © 1996 American Chemical Society

1126 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Mokrosz et al.
Sch em e 1a
Ch a r t 1
a
(i) n-BuOH, reflux, 13 h; (ii) N2H4‚H2O, EtOH, HCl, reflux, 4
h; (iii) xylene, reflux, 3 h.
Sch em e 2a
Ch a r t 2
a
(i) 1,4-Dibromobutane, KF/Al2O3, MeCN, reflux
4 h; (ii)
n-BuOH, K2CO3, reflux, 6 h.
Ta ble 1. 5-HT1A Binding Dataa (Ki) of the Investigated
Compounds 1-6 and 9
compd
Ki ( SEM (nM)
compd
Ki ( SEM (nM)
1b
2b
3
4
5a
12.3 ( 0.4
8.2 ( 2.4
6.4c
5b
6a
6b
6c
9
41 300 ( 9300
5.0 ( 0.2
140 ( 10
0.6c
2920 ( 90
1330 ( 80
>50 000c
a
b
Displacement of [3H]-8-OH-DPAT. The literature Ki data:
buspirone (1), 9.3-29.5 nM;9-12 BMY-7378, 2.40 nM.26 c The
following literature data were used for comparison: 3,27 4 (NAN-
190),17 and 9 (1,2,3,4-tetrahydroisoquinoline).22
Ta ble 2. Calculated van der Waals Volumes (V)a and
Hydrophobic Constants (log Pc)b for Cyclic Imides a -c (XH,
Chart 2)
cyclic imide
V (Å3)
log Pc
inhibition of the 8-OH-DPAT-induced behavioral syn-
drome in reserpinized rats (Table 3).2,30
a
b
c
126.8
104.1
68.1
-0.004
0.025
-2.235
Resu lts a n d Discu ssion
a
b
MOLSV (QCPE, Indiana University). PrologP 4.2 expert
The assessed 5-HT1A affinities of 1-3 are similar (Ki
) 6.4-12.3 nM, Table 1), though their structures are
substantially different. However, the literature data
indicated that enlargement of the succinimide moiety
of 327 with the benzene ring resulted in an enhanced
affinity of NAN-190 (4),17 which is a well-known post-
synaptic 5-HT1A antagonist.16 On the other hand,
replacement of the 1-(o-methoxyphenyl)piperazine frag-
ment by THIQ caused a dramatic loss of the 5-HT1A
affinity as was expected (cf. 2 vs 5a , 3 vs 6c, and 4 vs
6b, Table 1). As mentioned above, THIQ (9) did not
bind at 5-HT1A receptors (Table 1);23 hence, it may be
concluded that the 1-(o-methoxyphenyl)piperazine frag-
ment of the postsynaptic antagonists 2-4 plays a major
role in the formation of a bioactive complex with 5-HT1A
receptors. The latter conclusion is in a good agreement
with our previous findings that the methoxy group in
the arylpiperazine fragment is a desired feature of the
structure for both the affinity and postsynaptic antago-
nism at 5-HT1A receptors, shown by this class of
ligands.27,31,32 In marked contrast, the THIQ derivative
6a showed comparable 5-HT1A affinity with buspirone
(1). Therefore it may be anticipated that the buspirone
system (CompuDrug Ltd., Budapest, Hungary).
molecule is recognized by the receptor exclusively due
to the presence of a basic nitrogen atom and terminal
imide moiety.
The structure of the terminal imide fragment strongly
affects the 5-HT1A affinity of the THIQ derivatives 5 and
6. Therefore the volume (V) and/or lipophilicity (log Pc)
of the imide moiety may be regadred as the major
parameters that control the observed affinity changes.
The calculated V and log Pc values of the respective
imides a -c (XH in Chart 2) are given in Table 2. While
the lipophilicity of a and b is essentially the same, but
differs from that of c, the volume of a -c constantly
decreases. Thus it may be suggested that the 5-HT1A
affinity of 5a ,b and 6a -c depends on the volume of the
imide fragment rather than on their lipophilicity.
Indeed, the larger the volume, the higher the 5-HT1A
affinity. The above results are fully consistent with
some earlier findings of Glennon et al.14,33 and Orjales
et al.34 Having discussed a hypothetical model of 5-HT1A
sites, the former authors suggested that there should
exist a region of bulk tolerance adjoining the protonation

New Buspirone Analog as 5-HT1A Receptor Ligand
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1127
Ta ble 3. Induction of Lower Lip Retractiona (A) and the Behavioral Syndromeb (B) by Buspirone (1) and Its Analog 6a and Effect of
the Investigated Compounds on the 8-OH-DPAT-Induced Behavior in Reserpine-Pretreated Ratsc (C)
B: mean ( SEM behavioral score
C: mean ( SEM behavioral score
dose,
(mg/kg)
A: mean ( SEM,
treatment
LLR score
flat body posture
forepaw treading
flat body posture
forepaw treading
vehicle
buspirone (1)
0.1 ( 0.1
1.6 ( 0.2d
2.3 ( 0.2d
2.4 ( 0.2d
NT
0.2 ( 0.1
NT
0.2 ( 0.2
NT
NT
0.2 ( 0.2
0.6 ( 0.4
14.0 ( 0.5
NT
NT
13.2 ( 0.5
NT
1.25
2.5
5
NT
NT
6.8 ( 1.6d
6.4 ( 1.4d
14.3 ( 0.3
5.0 ( 0.9e
3.7 ( 0.6e
10
9.5 ( 1.5e
vehicle
6a
0.1 ( 0.1
1.2 ( 0.2d
1.9 ( 0.1d
2.5 ( 0.3d
NT
0.2 ( 0.1
NT
0.2 ( 0.2
NT
NT
2.0 ( 0.7
2.7 ( 1.4
14.5 ( 0.2
NT
NT
14.5 ( 0.6
13.7 ( 0.6
12.8 ( 0.7
NT
1.25
2.5
5
NT
NT
7.8 ( 1.5d
11.0 ( 0.7d
8.9 ( 1.1e
7.8 ( 1.2e
10
a
b
Buspirone (1) and 6a were administered ip 15 min before the test. Reserpine (1 mg/kg sc) and the investigated compounds were
administered 18 h and 3 min, respectively, before the test. c Reserpine (1 mg/kg sc) and the investigated compounds (ip) were administered
18 h and 15 min, respectively, before 8-OH-DPAT (5 mg/kg ip). p < 0.01 vs vehicle. e p < 0.01 vs vehicle + 8-OH-DPAT. NT ) not
d
tested.
site, which must be capable of accommodating bulky
groups such as those found in buspirone-like agents.14
In fact, other studies permitted a conclusion that large,
terminal amide substituents effectively increased the
5-HT1A affinity of some long-chain 1-arylpiperazines.33,34
If it is assumed that the proposed interaction mode
of buspirone with 5-HT1A receptors is correct, then its
analog 6a should retain not only the 5-HT1A affinity but
also the functional profile of buspirone at these recep-
tors. Both buspirone (1) and derivative 6a , injected in
doses of 1.25-5.0 mg/kg, induced dose-dependently the
LLR in rats, the maximum possible score being 80% and
83%, respectively, after the highest dose used (Table 3).
Essentially the same effect, characteristic of activation
of the postsynaptic 5-HT1A receptors, was reported by
Berendsen et al.6 for 8-OH-DPAT and buspirone. There-
fore it may be concluded that the two investigated
compounds, 1 and 6a , are equipotent agonists of post-
synaptic 5-HT1A receptors in the behavioral model
studied. Smith and Peroutka analyzed the effects of
8-OH-DPAT and buspirone on the behavioral syndrome
in normal rats.2 They showed that buspirone alone
evoked flat body posture but did not induce reciprocal
forepaw treading. In marked contrast, buspirone blocked
effectively the 8-OH-DPAT-induced forepaw treading
but not the flat body posture in normal rats.2 In the
present study we evaluated the effects of buspirone (1)
and compound 6a on the behavioral syndrome in reser-
pine-pretreated rats. Our results obtained for buspirone
are fully consistent with those discussed above (Table
3). Moreover, compound 6a showed a similar profile of
activity in those models. Buspirone (1) and its analog
6a , administered in doses of 10 mg/kg, induced flat body
posture in reserpinized rats, the maximum possible
score being 43% and 73%, respectively. However,
neither of the compounds produced forepaw treading
after the highest doses used (Table 3). Compounds 1
and 6a antagonized the 8-OH-DPAT-induced forepaw
treading by 72% and 39%, respectively. Moreover,
buspirone reduced the 8-OH-DPAT-induced flat body
posture only by 32%, whereas 6a failed to inhibit that
symptom.
pounds (1 and 6a ) may be classified as partial agonists
of postsynaptic 5-HT1A receptors. Furthermore, our
results may suggest that a basic nitrogen atom and
terminal, bulky cycloimide moiety, but not a 1-(2-
pyrimidinyl) substituent, are pivotal features of the
buspirone structure, which are directly responsible for
both the formation of the bioactive complex and its
functional profile at 5-HT1A receptors.
Exp er im en ta l Section
Ch em istr y. Melting points were determined on a Boetius
apparatus and are uncorrected. 1H NMR spectra were taken
with a Varian EM-360L (60 MHz) instrument in CDCl3
solution with Me4Si as an internal standard. Elemental
analyses were performed in the Institute of Organic Chemis-
try, Polish Academy of Sciences (Warsaw, Poland), and are
within (0.4% of the theoretical values.
The following compounds were commercial products: 7-9
and 13 (Aldrich) and 12 (Lancaster Syntheses). Compound 2
was obtained according to the described procedure.35
Gen er a l P r oced u r e. P r ep a r a t ion of Com p ou n d s 5b
a n d 6b. A mixture of N-(2-chloroethyl)- or N-(4-bromobutyl)-
phthalimide (3 mmol), 1,2,3,4-tetrahydroisoquinoline (0.4 g,
3 mmol), and n-butanol (30 mL) was refluxed for 13 h. Then
the reaction mixture was filtered off, and the solvent was
evaporated to give a crude product, which was purified by
crystallization.
2-(2-N-P h th a lim id oeth yl)-1,2,3,4-tetr a h yd r oisoqu in o-
lin e h yd r och lor id e (5b): yield 63%; mp 203-206 °C (EtOH);
1H NMR (base) δ 2.7-2.95 (m, 6 H, 3 CH2), 3.7 (s, 2 H, CH2),
3.9 (t, 2 H, CH2, J ) 7 Hz), 7.1 (s, 4 H arom), 7.5-7.9 (m, 4 H
arom). Anal. (C19H18N2O2‚HCl) C, H, N.
2-(4-N-P h th a lim id obu tyl)-1,2,3,4-tetr a h yd r oisoqu in o-
lin e h yd r obr om id e (6b): yield 55%; mp 233-235 °C (MeOH);
1H NMR (base) δ 1.5-1.9 (m, 4 H, 2 CH2), 2.4-3.0 (m, 6 H, 3
CH2), 3.55 (s, 2 H, CH2), 3.7 (t, 2 H, CH2, J ) 7 Hz), 6.9-7.2
(m, 4 H arom), 7.6-8.0 (m, 4 H arom). Anal. (C21H22N2O2‚
HBr) C, H, N.
Gen er a l P r oced u r e. P r ep a r a t ion of Com p ou n d s 5a
a n d 6a . A solution of 5b or 6b (free bases, 1.2 mmol) and
hydrazine (0.5 mL, 15 mmol) in 99.8% ethanol (15 mL) was
refluxed for 1 h. The reaction mixture was cooled down and
treated with an additional amount of 99.8% ethanol (15 mL)
and concentrated HCl (1.3 mL). Then the reaction mixture
was refluxed for 4 h and left overnight in a refrigerator. The
precipitate was filtered off, and the solvent was evaporated.
The residue was treated with n-hexane (20 mL) and NH3
(aqueous, 15 mL). The solution was extracted with CHCl3 (3
× 15 mL), the organic layer was dried over anhydrous K2CO3,
and the solvents were evaporated to give a product which was
used without further purification.
In conclusion, it should be stressed that replacement
of the 1-(2-pyrimidinyl)piperazine fragment in buspirone
by the 1,2,3,4-tetrahydroisoquinoline ring system, which
yielded the model compound 6a , did not significantly
affect either the observed 5-HT1A affinity or the func-
tional profile at those receptors. Both of these com-
2-(2-Am in oeth yl)-1,2,3,4-tetr a h yd r oisoqu in olin e (10):
yield 76%; 1H NMR δ 1.85 (t, 2 H, NH2, J ) 10 Hz), 2.55-3.2
(m, 8 H, 4 CH2), 3.6 (s, 2 H, CH2), 6.9-7.2 (m, 4 H arom).

1128 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Mokrosz et al.
2-(4-Am in obu tyl)-1,2,3,4-tetr a h yd r oisoqu in olin e (11):
yield 83%; 1H NMR δ 1.2-1.75 (m, 6 H, NH2, 2 CH2), 2.3-3.0
(m, 8 H, 4 CH2), 3.6 (s, 2 H, CH2), 6.9-7.2 (m, 4 H arom).
A solution of 10 or 11 (1 mmol) and anhydride 12 (0.17 g, 1
mmol) in dry xylene (15 mL) was refluxed for 3 h. Then the
solvent was evaporated, and the residue was purified using
column chromatography (SiO2, CHCl3-MeOH, 95:5). Free
bases were dissolved in acetone (5-7 mL), treated with an
excess of diethyl ether saturated with dry, gaseous HCl, and
kept in a refrigerator to yield colorless, crystalline products.
8-[2-[2-(1,2,3,4-Te t r a h yd r oisoq u in olin yl)]e t h yl]-8-
a za sp ir o[4.5]d eca n e-7,9-d ion e h yd r och lor id e (5a ): yield
37%; mp 183-185 °C; 1H NMR (base) δ 1.4-1.7 (m, 8 H, 4
CH2), 2.6 (s, 4 H, 2 CH2CO), 2.65-2.8 (m, 6 H, 3 CH2), 3.65 (s,
2 H, CH2), 4.0 (t, 2 H, CH2, J ) 7 Hz). Anal. (C20H26N2O2‚
HCl‚H2O) C, H, N.
to 15/animal/symptom.30 The effect of 6a and buspirone on
the behavioral syndrome induced by 8-OH-DPAT (5 mg/kg ip)
in reserpinized rats was estimated in an independent experi-
ment. Compound 6a and buspirone were administered ip 15
min before 8-OH-DPAT. Observations began 3 min after
8-OH-DPAT administration and were repeated every 3 min
for a period of 15 min.
Sta tistics. The obtained data were analyzed by Dunnett’s
test.
Ack n ow led gm en t. Mr. A. J . Bojarski is a fellowship
holder of the Foundation for the Polish Sciences (1995).
Refer en ces
(1) Goa, K.; Ward, A. Buspirone - a preliminary review on its
pharmacological properties and therapeutic efficacy as an anxio-
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(2) Smith, L. M.; Peroutka, S. J . Differential effects of 5-hydroxy-
tryptamine1A selective drugs on the 5-HT behavioral syndrome.
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(3) Andrade, R.; Nicoll, R. A. Novel anxiolytics discriminate between
postsynaptic serotonin receptors mediating different physiologi-
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(5) Przegalin´ski, E.; Tatarczyn´ska, E.; Chojnacka-Wo´jcik, E. Anti-
conflict effect of ipsapirone, buspirone and gepirone is not
mediated by their common metabolite 1-(2-pyrimidinyl)piper-
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activation of 5-HT1A receptors induces lower lip retraction in the
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depressant-like activity of ipsapirone, buspirone and gepirone
in the forced swimming test in rats pretreated with proadifen.
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283-326.
8-[4-[2-(1,2,3,4-Te t r a h yd r oisoq u in olin yl)]b u t yl]-8-
a za sp ir o[4.5]d eca n e-7,9-d ion e h yd r och lor id e (6a ): yield
1
32%; mp 160-162 °C; H NMR (base) δ 1.3-1.9 (m, 12 H, 6
CH2), 2.55 (s, 4 H, 2 CH2CO), 2.3-3.0 (m, 6 H, 3 CH2), 3.65 (s,
2 H, CH2), 3.95 (t, 2 H, CH2, J ) 7 Hz), 7.0-7.3 (m, 4 H arom).
Anal. (C22H30N2O2‚HCl‚0.5H2O) C, H, N.
2-(4-N-Su ccin im id obu tyl)-1,2,3,4-tetr a h yd r oisoqu in o-
lin e Hyd r och lor id e (6c). A mixture of succinimide (0.2 g, 2
mmol), 1,4-dibromobutane (0.43 g, 2 mmol), KF/Al2O3 catalyst
(2 g), and acetonitrile (15 mL) was refluxed for 4 h and left
overnight at room temperature. Then the inorganic precipitate
was filtered off, and the solvent was evaporated to give N-(4-
1
bromobutyl)succinimide (14): yield 69%, oil; H NMR δ 1.7-
2.2 (m, 4 H, 2 CH2), 2.75 (s, 4 H, 2 CH2), 3.35-3.7 (m, 4 H, 2
CH2).
A mixture of 14 (0.29 g, 1 mmol), 1,2,3,4-tetrahydroiso-
quinoline (0.17 g, 1.3 mmol), K2CO3 (0.5 g), and n-butanol (10
mL) was refluxed for 6 h and left overnight at room temper-
ature. Then the inorganic precipitate was filtered off, the
solvent was evaporated, and the residue was purified using
silica gel chromatography (Chromatotron) and CHCl3 as an
eluent. The product was converted into HCl salt as described
(9) Piercey, M. F.; Smith, M. W.; Lum-Ragan, J . T. Excitation of
noradrenergic cell firing by 5-hydroxytryptamine1A agonists
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1
above: yield 55%; mp 187-190 °C (acetone); H NMR (base)
(10) Zifa, E.; Fillion, E. 5-Hydroxytryptamine receptors. Pharmacol.
Rev. 1992, 44, 401-458.
δ 1.5-1.9 (m, 4 H, 2 CH2), 2.65 (s, 4 H, 2 CH2), 2.4-3.1 (m, 6
H, 3 CH2), 3.4-3.75 (m, 4 H, 2 CH2), 7.0-7.25 (m, 4 H arom).
Anal. (C17H22N2O2‚HCl) C, H, N.
(11) Van Wijngaarden, I.; Tulp, M. T. M.; Soudijn, W. The concept of
selectivity in 5-HT receptor research. Eur. J . Pharmacol.-Mol.
Pharmacol. Sect. 1990, 188, 301-312.
Ra d ioliga n d Bin d in g Exp er im en ts. Radioligand binding
studies with 5-HT1A receptors were conducted in the rat brain
(hippocampus) according to the published procedure.36 The
radioligand used in the binding assays was [3H]-8-OH-DPAT
(190 Ci/mmol, Amersham). The Ki values were determined
from at least three competition binding experiments in which
10-14 drug concentrations, run in triplicate, were used.
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