Synthesis and structure-affinity relationships of 1-[ω-(4-aryl-1-piperazinyl)alkyl]-1-aryl ketones as 5-HT7 receptor ligands

Article abstract of DOI:10.1021/jm020994z

Structural requirements for 5-HT₇ receptor affinity and selectivity over that for the 5-HT_1A receptor were studied on a series of 1-[ω-(4-aryl-1-piperazinyl)alkyl]-1-aryl ketones. The presence of a hydroxy or methoxy substituent on aryl ketone moiety, alkyl chain length, and the nature of N-1-piperazine substituent were explored. 6-[4-(3-Benzisoxazolyl)-1-piperazinyl]-1-(2-hydroxyphenyl)-1-hexanone (40) and its methoxy analogue 43 exhibited high 5-HT₇ receptor affinities (K_i = 2.93 nM and 0.90 nM, respectively) and agonist properties when tested for 5-HT₇ receptor-mediated relaxation of substance P-induced guinea-pig ileum contraction.

Full text of DOI:10.1021/jm020994z

646
J . Med. Chem. 2003, 46, 646-649
Syn th esis a n d Str u ctu r e-Affin ity Rela tion sh ip s of
1-[ω-(4-Ar yl-1-p ip er a zin yl)a lk yl]-1-a r yl Keton es a s 5-HT7 Recep tor Liga n d s
Roberto Perrone,* Francesco Berardi, Nicola A. Colabufo, Enza Lacivita, Marcello Leopoldo, and
Vincenzo Tortorella
Dipartimento Farmaco-Chimico, Universita` degli Studi di Bari, via Orabona, 4, 70126, Bari, Italy
Received J uly 12, 2002
Structural requirements for 5-HT7 receptor affinity and selectivity over that for the 5-HT1A
receptor were studied on a series of 1-[ω-(4-aryl-1-piperazinyl)alkyl]-1-aryl ketones. The presence
of a hydroxy or methoxy substituent on aryl ketone moiety, alkyl chain length, and the nature
of N-1-piperazine substituent were explored. 6-[4-(3-Benzisoxazolyl)-1-piperazinyl]-1-(2-hy-
droxyphenyl)-1-hexanone (40) and its methoxy analogue 43 exhibited high 5-HT7 receptor
affinities (Ki ) 2.93 nM and 0.90 nM, respectively) and agonist properties when tested for
5-HT7 receptor-mediated relaxation of substance P-induced guinea-pig ileum contraction.
Ch a r t 1
Serotonin (5-HT) is involved in various physiological
and pathological processes by interaction with seven
classes of receptors (5-HT1-7), containing 14 distinct
receptors grouped on the basis of amino acid sequence,
pharmacology, and signal transduction pathways.1,2 The
5-HT7 receptor was found by the application of molec-
ular cloning and has been identified in rat,3-5 mouse,6
human,7 and guinea pig.8 Although the biological func-
tions of the 5-HT7 receptor are poorly understood,
preliminary evidence suggests that it may be involved
in depression,9,10 control of circadian rhythms,11 and
relaxation of vascular smooth muscle.12,13 Clearly, the
5-HT7 receptor may be a valuable novel drug target. To
examine this possibility, the development of potent
and selective ligands for the 5-HT7 receptor is highly
desired. To date a limited number of papers dealing with
the research of selective 5-HT7 ligands has been
published.14-21 Kikuchi15,21 and Lopez-Rodriguez16 re-
ported some arylpiperazine derivatives sharing some
structural features with “long-chain” arylpiperazines,
a well-known class of 5-HT1A receptor ligands. In
particular, 1-(2-methoxyphenyl)piperazine derivatives
115 and 216 (Chart 1) were reported as 5-HT7 receptor
ligands (Ki ) 5.1 nM and Ki ) 63 nM, respectively).
These findings have prompted us to test on a rat cloned
5-HT7 receptor several derivatives previously studied22-26
as 5-HT1A or D4 ligands, characterized by a 1-(2-
methoxyphenyl)piperazinyl group joined by a spacer to
an aromatic structure. In this way, we have identified
compounds 3 and 426 (Table 1) possessing moderate
5-HT7 receptor affinities (Ki ) 109 nM and Ki ) 85 nM,
respectively). Unfortunately, they proved to be high-
affinity 5-HT1A receptor ligands (Ki ) 0.78 nM and Ki
) 3.4 nM, respectively). Therefore, we developed novel
compounds by modifying the structure of 4, having as
a primary goal the improvement of the 5-HT7 receptor
affinity.
tones 9-22. Derivatives 9-12 were prepared from
benzaldehydes 5a ,b that were reacted with the ap-
propriate Grignard reagent to give benzyl alcohols 6a ,b
and 7a ,b. Oxidation of these latter compounds with
J ones reagent afforded ketones 9-12.27 Ketone 13 was
obtained following a previously reported procedure.27
Aldehyde 5a was reacted with trimethylsilyl cyanide to
give the trimethylsilyl cyanohydrin 8. This latter com-
pound was transformed into its anion with lithium
diisopropylamide (LDA) and then was alkylated with
1-bromo-3-chloropropane. The protected cyanohydrin so
obtained gave ketone 13 by treating with dilute HCl.
Phenolic derivatives 14-18 were prepared from the
corresponding methoxy derivatives 9-13 by cleavage of
the ether bond with concentrated HBr. Phenyl or
4-hydroxyphenyl ketones 19-22 were prepared accord-
ing to literature methods by a Friedel-Crafts acyla-
tion.28 Final compounds 23-43 were achieved by react-
ing ω-haloalkyl ketones 10, 12, and 14-22 with the
appropriate 1-substituted piperazine. These latter in-
termediates were obtained from commercial sources or
were prepared by literature methods as detailed in the
Experimental Section (see Supporting Information).
Resu lts a n d Discu ssion
The results of the binding assays on 5-HT7 and 5-HT1A
receptors are listed in Table 1. The first modification of
4 was the elongation of the intermediate alkyl chain
from four to five methylenes (compound 23). 5-HT7
affinity values of compounds 3, 4, and 23 showed that
affinity was increased by alkyl chain elongation. This
result suggested that the alkyl chain length of these
compounds is important in determining the affinity for
Ch em istr y
The preparation of the final compounds (Scheme 1)
required the key intermediate ω-haloalkylphenyl ke-
* To whom correspondence should be addressed. Phone: +39-080-
5442752. Fax: +39-080-5442231. E-mail: perrone@farmchim.uniba.it.
10.1021/jm020994z CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/18/2003

Brief Articles
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4 647
Ta ble 1. Binding Affinities of Final Compoundsa
Sch em e 1a
a
Reagents: (A) Bromo(4-chlorobutyl)magnesium or bromo(5-
chlorobutyl)magnesium; (B) J ones reagent; (C) trimethylsilyl
cyanide, ZnI2; (D) i. LDA; ii. 1-bromo-3-chloropropane; iii. 2 N HCl;
(E) 48% HBr; (F) ω-haloacyl chloride, AlCl3; (G) 1-substituted
piperazine.
Ch a r t 2
5-HT7 affinity. Moreover, a clear trend was not shown,
because when n ) 5 the 2-hydroxy derivative 30 showed
the higher 5-HT7 affinity value, whereas when n ) 4,
the 2- and 3-hydroxy-substituted derivatives 28 and 24,
respectively, were equipotent. Although compounds 23-
31 displayed improved 5-HT7 affinity values (Kis rang-
ing between 5.8 nM and 59.1 nM) compared to the
starting compounds 3 and 4, they all showed higher
5-HT1A affinity than 5-HT7 affinity, except compound
30 (Ki ) 5.8 nM on both receptors). This latter com-
pound was chosen for further structural modifications
because it was the only one of this series showing
nanomolar 5-HT7 receptor affinity. The lack of selectiv-
ity over 5-HT1A receptors of compounds 23-31 should
be due to the 2-methoxyphenyl group linked to N-1
position of the piperazine ring. In fact, well-known
5-HT1A receptor ligands such as WAY-100635 and NAN-
190 (Chart 2) are 1-(2-methoxyphenyl)piperazine de-
rivatives.29 Therefore, we replaced the 2-methoxyphenyl
group with a variety of substituents, including certain
groups that were expected not to lead to 5-HT1A ligands
a
Receptors and radioligand used in binding assays: 5-HT7 (rat
cloned receptors in HEK-293 cells; [3H]LSD); 5-HT1A (rat hippo-
campus membranes, [3H]-8-OH-DPAT). Full Ki not obtained,
b
percentage inhibition at the concentration shown given in paren-
theses.
the 5-HT7 receptor. Therefore, the next modifications
were limited to compounds having n ) 4 or n ) 5. Then,
an initial investigation on the nature of the substituent
required on the aromatic ring attached to the carbonyl
function was accomplished by removal or demethylation
of methoxy substituent (compounds 24-27). Both modi-
fications resulted in a slight increase in 5-HT7 affinity,
but did not give any insight on the role of those
substituents on the aromatic ring. However, 3-hydroxy
derivative 24 displayed higher 5-HT7 receptor affinity
than the corresponding 3-methoxy derivative 4 and, for
this reason, we also investigated the 2- and 4-hydroxy-
substituted derivatives 28-31. The position of the
hydroxy substituent seems to have a marginal role on

648 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4
Brief Articles
Ta ble 3. Comparison between Maximal Relaxation Effects
Induced by 5-CT, 40, and 43 on Substance P-stimulated Guinea
Pig Ileum Contracture with or without 5-HT7 Receptor
Desensitization
Ta ble 2. Extended Binding Screening of Compounds 40 and
43a
Ki ( SEM, nM
receptor
40
43
% relaxation (( SEM)
5-HT7
5-HT1A
5-HT2A
D2L
D3
D4
2.93 ( 0.22
0.90 ( 0.05
5-HT7
5-HT7
189 ( 12
175 ( 20
compd
dose, µM
nondesensitized
desensitized
7.97 ( 0.24
246 ( 15
9.03 ( 0.71
78.1 ( 8.3
5-CT
40
43
3
3
3
39 ( 3
43 ( 4
38 ( 2
no response
no response
no response
361 ( 25
318 ( 20
96 ( 5
61 ( 8
182 ( 19
54.9 ( 8.2
3.94 ( 0.45
0.41 ( 0.05
4295 ( 150
147 ( 18
R1
σ1
Ch a r t 3
σ2
a
Receptors and radioligand used in binding assays: 5-HT2A
(rat cortex membranes; [3H]ketanserin), D2L (human cloned
receptors in Sf9 cells; [3H]spiroperidol); D3 (rat cloned receptors
in Sf9 cells; [3H]spiroperidol); D4 (human cloned receptors in CHO
cells; [3H]spiroperidol); R1 (rat cortex membranes; [3H]prazosin);
σ1 (guinea-pig brain membranes without cerebellum; [3H]-(+)-
pentazocine); σ2 (rat liver membranes, [3H]DTG).
Compounds 40 and 43 were tested for 5-HT7 intrinsic
activity in an isolated guinea-pig ileum preparation
along with 5-HT7 receptor agonist 5-CT [5-carboxamido-
tryptamine]. It has been reported that 5-HT7 agonists
can produce dose-dependent guinea-pig ileum relaxation
of substance P-induced contraction.36,37 EC50 values of
5-CT, 40, and 43 were found to be 0.63 µM, 0.37 µM,
and 0.18 µM, respectively. Compounds 40 and 43
behaved as 5-HT7 competitive agonists such as 5-CT
because (a) they did not induce relaxation when 5-HT7
receptors were desensitized by 5-CT (Table 3); (b) the
selective 5-HT7 antagonist SB-269970 (Chart 3) was
able to revert their effects by shifting to the right the
corresponding concentration-response curve in a sur-
mountable manner. The slope of Schild plots (95%
confidence intervals) of 5-CT, 40, and 43 were 1.2 (1.0-
1.4), 1.1 (1.0-1.2), and 1.0 (0.9-1.1), respectively. pA2
values of 5-CT, 40, and 43 were 7.48 ( 0.12 (n ) 12),
7.54 ( 0.24 (n ) 12), and 7.62 ( 0.30 (n ) 22),
respectively.
In conclusion, structural modifications on known D4
ligands (compounds 3 and 4) led to the identification of
several 1-[ω-[4-(2-methoxyphenyl)-1-piperazinyl)alkyl]-
1-aryl ketones having good 5-HT7 receptor affinity, but
poor selectivity over 5-HT1A receptor. Further modifica-
tions led to 6-[4-(3-benzisoxazolyl)-1-piperazinyl]-1-
(2-hydroxyphenyl)-1-hexanone (40) and 6-[4-(3-benz-
isoxazolyl)-1-piperazinyl]-1-(2-methoxyphenyl)-1-hex-
anone (43) that exhibited high 5-HT7 receptor affinity
(Ki ) 2.93 nM and 0.90 nM, respectively). Although 40
and 43 showed good selectivity over 5-HT1A receptor,
they were poorly selective over 5-HT2A receptor. More-
over, derivatives 40 and 43 displayed agonist properties
such as 5-CT when tested for 5-HT7 receptor-mediated
relaxation of substance P-induced guinea-pig ileum
contraction.
(i.e., 1,2-benzisoxazol-3-yl,30 methyl,31cyclohexyl31). This
modification was not tolerated. In fact, compounds 32-
39 showed lower 5-HT7 affinity than the 2-methoxy-
phenyl derivative 30. In particular, the absence of an
aromatic ring linked to the piperazine ring caused a
complete loss of 5-HT7 affinity (methyl and cyclohexyl
derivatives 32 and 33, respectively). The only exception
was compound 40 that showed a slight increase in 5-HT7
affinity as compared to 30, along with the expected
marked decrease in 5-HT1A receptor affinity. Compound
40 was identified as a high-affinity 5-HT7 receptor
ligand (Ki ) 2.93 nM), 65-fold selective over 5-HT1A
receptors. It is noteworthy that compound 39 differs
from 40 by the presence of a methoxy in 5-position of
the 1,2-benzisoxazole ring and this caused a drop in
5-HT7 affinity. This unexpected result could suggest that
this part of the molecule is quite sensitive to minimal
structural changes. However, this hypothesis will be
verified in future studies. Next, we evaluated the lower
homologues of 40 (compounds 41 and 42, having n ) 3
and n ) 4, respectively), and 5-HT7 affinity data
confirmed that a five-methylene chain was preferred.
Encouraged by the high 5-HT7 affinity of 40, we also
prepared the corresponding methoxy derivative 43 to
obtain a potential PET radioligand, when 11C labeled
in the O-methyl position. Surprisingly, 43 showed
higher 5-HT7 affinity than the phenol 40.
Consequently, compounds 40 and 43 were tested
against a panel of receptors capable of binding 4-sub-
stituted-1-arylpiperazines (Table 2), but results were
disappointing. Compounds 40 was found to have low
affinity for D2, D3, D4, and σ2 receptors (Kis > 100 nM),
moderate affinity for R1 and σ1 receptors (Ki ) 96 nM
and 61 nM, respectively), and high 5-HT2A receptor
affinity (Ki ) 8.0 nM). σ1 Receptor affinity could depend
on some structural features shared with butyrophe-
nones, a class of compounds reported to bind at σ1
receptors.32-34 5-HT2A receptor affinity could be ex-
plained by the presence of the 3-(1-piperazinyl)-1,2-
benzisoxazole moiety which is closely related to the 3-(1-
piperidinyl)-1,2-benzisoxazole moiety contained by the
5-HT2A agent risperidone.35 Compound 43 showed an
even worse binding profile than 40, being nonselective
over 5-HT2A, D4, and R1 receptors. For this reason 43
cannot be proposed as a potential PET radioligand.
Ack n ow led gm en t. This study was supported by
Research Grant No. 2001037552-003 from Universita`
degli Studi di Bari and MURST (Italy) for the scientific
program in CO7X field (2002-2003).
Su p p or tin g In for m a tion Ava ila ble: Physical and spec-
tral data of all the synthesized compounds; experimental
procedure for synthesis and biological evaluation. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.

Brief Articles
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4 649
(20) Rezaie, R.; J oseph, B.; Bremner, J . B.; Delagrange, P.; Kopp,
C.; Misslin, R.; Pfeiffer, B.; Renard, P.; Guillaumet, G. 5-Sub-
stituted 3,4-dihydro-3-amino-2H-1-benzopyran derivatives: syn-
thesis and interaction with serotoninergic receptors. J . Pharm.
Pharmacol. 2001, 53, 959-668.
(21) Kikuchi, C.; Ando, T.; Watanabe, T.; Nagaso, H.; Okuno, M.;
Hiranuma, T.; Koyama, M. 2a-[4-(Tetrahydropyridoindol-2-yl)-
butyl]tetrahydrobenzindole derivatives: new selective antago-
nists of the 5-hydroxytryptamine7 receptor. J . Med. Chem. 2002,
45, 2197-2206.
(22) Perrone, R.; Berardi, F.; Colabufo, N. A.; Tortorella, V.;
Fiorentini, F.; Olgiati, V.; Vanotti, E.; Govoni, S. Mixed
5-HT1A/D-2 activity of a new model of arylpiperazine: 1-aryl-4-
[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines. 1. Syn-
thesis and structure-activity relationships. J . Med. Chem. 1994,
37, 99-104.
(23) Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.; Tortorella,
V.; Fiorentini, F.; Olgiati, V.; Ghiglieri, A.; Govoni, S. High
affinity and selectivity on 5-HT1A receptor of 1-aryl-4-[(1-tetra-
lin)alkyl]piperazines. 2. J . Med. Chem. 1995, 38, 942-949.
(24) Perrone, R.; Berardi, F.; Leopoldo, M.; Tortorella, V.; Lograno,
M. D.; Daniele, E.; Govoni, S. 5-HT1A and D-2 receptor affinity
of o-methoxyphenylpiperazine derivatives with terminal benza-
mide fragment on N-4 alkyl chain. 2. Farmaco 1995, 50, 505-
510.
(25) Perrone, R.; Berardi, F.; Leopoldo, M.; Tortorella, V.; Fornaretto,
M. G.; Caccia, C.; McArthur, R. 1-Aryl-4-[(1-tetralinyl)alkyl]-
piperazines: alkylamido and alkylamino derivatives. Synthesis,
5-HT1A receptor affinity, and selectivity. 3. J . Med. Chem. 1996,
39, 3195-3202.
(26) Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.; Tortorella,
V. 1-(2-Methoxyphenyl)-4-alkylpiperazines: effect of the N-4
substituent on the affinity and selectivity for dopamine D4
receptor. Bioorg. Med. Chem. Lett. 1997, 7, 1327-1330.
(27) Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.; Tortorella,
V. A structure-affinity relationship study on derivatives of N-[2-
[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a
high-affinity and selective D4 receptor ligand. J . Med. Chem.
2000, 43, 270-277.
(28) Kawakita, T.; Kuriota, T.; Murozono, T.; Hakira, H.; Haga, K.;
Ito, K.; Sonda, S.; Kawahara, T.; Asano, K. Preparation of 5-HT4
agonist 4-amino-N-(piperidinylalkyl)benzamides and analogues
as gastrointestinal drugs. US 5864039A, 1999.
(29) Cliffe, I. A.; Fletcher, A. Advances in 5-HT1A antagonist research.
Drugs Future 1993, 18, 631-642.
(30) Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.; Tortorella,
V. 1-Substituted-4-[3-(1,2,3,4-tetrahydro-5- or 7-methoxynaph-
thalen-1-yl)propyl]piperazines: influence of the N-1 piperazine
substituent on 5-HT1A receptor affinity and selectivity versus
D2 and R1 receptors. 6. Bioorg. Med. Chem. 2000, 8, 873-881.
(31) Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.; Abate,
C.; Tortorella, V. N-aryl- or N-alkylpiperazine derivatives: the
role of N-substituent on σ1, σ2, 5-HT1A and D2 receptor affinity.
Med. Chem. Res. 2000, 10, 201-207.
(32) Glennon, R. A.; Ablordeppey, S. Y.; Ismaiel A. M.; El-Ashmawy
M. B.; Fischer, J . B.; Burke Howie, K. Structural features
important for σ1 receptor binding. J . Med. Chem. 1994, 37,
1214-1219.
(33) Ablordeppey, S. Y.; Issa, H.; Fischer, J . B.; Burke Howie, K. J .;
Glennon R. A. Synthesis and structure-affinity relationship
studies of sigma ligands related to haloperidol. Med. Chem. Res.
1993, 3, 131-138.
(34) J aen, J . C.; Caprathe, B. W.; Pugsley T. A.; Wise, L. D.; Akunne
H. Evaluation of the effects of the enantiomers of reduced
haloperidol, azaperol and related 4-amino-1-arylbutanols on
dopamine and σ receptors. J . Med. Chem. 1993, 36, 3929-3936.
(35) Megens, A. A. H. P.; Kennis, L. E. J . Risperidone and related
5HT2/D2 antagonists: a new type of antipsychotic agent? Prog.
Med. Chem. 1996, 33, 185-232.
Refer en ces
(1) Uphouse, L. Multiple serotonin receptors: too many, not enough,
or just the right number? Neurosci. Biobehav. Rev. 1997, 21,
679-698.
(2) Saxena, P. R. Serotonin receptors: subtypes, functional re-
sponses and therapeutic relevance. Pharmacol. Ther. 1995, 339-
368.
(3) Shen, Y.; Monsma, F. J .; Metcalf, M. A.; J ose, P. A.; Hamblin,
M. W.; Sibley, D. R. Molecular cloning and expression of a 5-HT7
serotonin receptor subtype. J . Biol. Chem. 1993, 268, 18200-
18204.
(4) Lovenberg, T. W.; Baron, B. M.; de Lecea, L.; Miller, J . O.;
Prosser, R. A.; Rea, M. A.; Foye, P. E.; Rucke, M.; Slone, A. L.;
Siegel, B. W.; Danielson, P. E.; Sutcliffe, J . G.; Erlander, M. G.
A novel adenyl cyclase-activating serotonin receptor (5-HT7)
implicated in the regulation of mammalian circadian rhythms.
Neuron 1993, 11, 449-458.
(5) Ruat, M.; Traiffort, E.; Leurs, R.; Tardivel-Lacombe, J .; Diaz,
J .; Arrang, L. M.; Schwartz, J . C. Molecular cloning, character-
ization and localization of a high-affinity serotonin receptor (5-
HT7) activating cAMP formation. Proc. Natl. Acad. Sci. U.S.A.
1993, 90, 8547-8551.
(6) Plassat, J .-L.; Amlaiky, N.; Hen, R. Molecular cloning of a
mammalian serotonin receptor that activates adenylate cyclase.
Mol. Pharmacol. 1993, 44, 229-236.
(7) Bard, J . A.; Zgombick, J .; Adham, N.; Vaysse, P.; Branchek, T.
A.; Weinshank, R. L. Cloning of novel human serotonin receptor
(5-HT7) positively linked to adenylate cyclase. J . Biol. Chem.
1993, 268, 23422-23426.
(8) Tsou, A.-p.; Kosaka, A.; Bach, C.; Zuppan, P.; Yee, C.; Tom, L.;
Alvarez, R.; Ramsey, S.; Bonhaus, D. W.; Stefanich, E.; J akeman,
L.; Eglen, R. M.; Chan, H. W. Cloning and expression of a
5-hydroxytryptamine7 receptor positively coupled to adenylyl
cyclase. J . Neurochem. 1994, 63, 456-464.
(9) Yau, J . L.; Noble, J .; Widdowson, J .; Seckl, J . R. Impact of
adrenalectomy on 5-HT6 and 5-HT7 receptor gene expression in
the rat hippocampus. Brain Res. Mol. Brain Res. 1997, 45, 182-
186.
(10) Shimizu, M.; Nishida, A.; Zensho, H.; Yamawaki, S. Chronic
antidepressant exposure enhances 5-hydroxytryptamine7 recep-
tor-mediated cyclic adenosine monophosphate accumulation in
rat frontocortical astrocytes. J . Pharmacol. Exp. Ther. 1996, 279,
1551-1558.
(11) Ying, S. W.; Rusak, B. 5-HT7 receptors mediate serotonergic
effects on light-sensitive suprachiasmatic nucleus neurons. Brain
Res. 1997, 755, 246-254.
(12) Terron, J . A.; Falcon-Neri, A. Pharmacological evidence for the
5-HT7 receptor mediating smooth muscle relaxation in canine
cerebral arteries. Br. J . Pharmacol. 1999, 127, 609-616.
(13) De Vries, P.; De Visser, P. A.; Heiligers, J . P.; Villalon, C. M.;
Saxena, P. R. Changes in systemic and regional haemodynamics
during 5-HT7 receptor-mediated depressor responses in rats.
Naunyn-Schmiedeberg’s Arch. Pharmacol. 1999, 359, 331-338.
(14) Forbes, I. T.; Dabbs, S.; Duckworth, D. M.; J ennings, A. J .; King,
F. D.; Lovell, P. J .; Brown, A. M.; Collin, L.; Hagan, J . J .;
Middlemiss, D. N.; Riley, G. J .; Thomas, D. R.; Upton, N. (R)-
3,N-dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]ben-
zenesulfonamide: the first selective 5-HT7 receptor antagonist.
J . Med. Chem. 1998, 41, 655-657.
(15) Kikuchi, C.; Nagaso, H.; Hiranuma, T.; Koyama, M. Tetrahy-
drobenzindoles: selective antagonists of the 5-HT7 receptor. J .
Med. Chem. 1999, 42, 533-535.
(16) Lo´pez-Rodr´ıguez, M. L.; Porras, E.; Benhamu´, B.; Ramos, J . A.;
Morcillo, M. J .; Lavandera, J . L. First pharmacophoric hypoth-
esis for 5-HT7 antagonism. Bioorg. Med. Chem. Lett. 2000, 10,
1097-1100.
(17) Lovell, P. J .; Bromidge, S. M.; Dabbs, S.; Duckworth, D. M.;
Forbes, I. T.; J ennings, A. J .; King, F. D.; Middlemiss, D. N.;
Rahman, S. K.; Saunders, D. V.; Collin, L. L.; Hagan, J . J .; Riley,
G. J .; Thomas, D. R. A novel, potent, and selective 5-HT7
antagonist: (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-
1-sulfonyl)phenol (SB-269970). J . Med. Chem. 2000, 43, 342-
345.
(18) Linnanen, T.; Brisander, M.; Mohell, N.; J ohansson, A. M.
Serotonergic and dopaminergic activities of rigidified (R)-apor-
phine derivatives. Bioorg. Med. Chem. Lett. 2001, 11, 367-370.
(19) Linnanen, T.; Brisander, M.; Unelius, L.; Rosqvist, S.; Nordvall,
G.; Hacksell, U.; J ohansson, A. M. Atropisomeric derivatives of
2′,6′-disubstituted (R)-11-phenylaporphine: selective serotonin
5-HT7 receptor antagonists. J . Med. Chem. 2001, 44, 1337-1340.
(36) Carter, D.; Champney, M.; Hwang, B.; Eglen, R. M. Character-
ization of a postjunctional 5-HT receptor mediating relaxation
of guinea-pig isolated ileum. Eur. J . Pharmacol. 1995, 280, 243-
250.
(37) Lucchelli, A.; Santagostino-Barbone, M. G.; D’Agostino, G.;
Masoero, E.; Tonini, M. The interaction of antidepressant drugs
enteric 5-HT7 receptors. Naunyn-Schmiedeberg’s Arch. Phar-
macol. 2000, 362, 284-289.
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