4-fluoro-5-methoxy-pyrrolidine-tryptamine, biotransformation
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Bioorganic & Medicinal Chemistry Letters 11 (2001) 793–795
ANovelFluorinatedTryptaminewithHighlyPotentSerotonin
5-HT
1A
ReceptorAgonistProperties
Urosˇ Laban, Deborah Kurrasch-Orbaugh, Danuta Marona-Lewicka
and David E. Nichols*
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences,
Purdue University, West Lafayette, IN 47907-1333, USA
Received 4 December 2000; accepted 23 January 2001
Abstract—Synthesis and biological evaluation of a novel fluorinated tryptamine analogue are described. This new compound 1-(4-
fluoro-5-methoxyindol-3-yl)pyrrolidine (2) was found to be a potent serotonin 5-HT
1A
agonist. # 2001 Elsevier Science Ltd. All
rights reserved.
Recently
1
we reported on several fluorinated trypta-
mines. One of them, 4-fluoro-5-methoxy-N,N-dimethyl-
tryptamine 1, proved to be a potent serotonin 5-HT
1A
agonist. Substitution with the 4-fluorine markedly
increased 5-HT
1A
selectivity over 5-HT
2A/2C
receptors.
In view of widespread interest in the function of 5-HT
1A
receptors in the central nervous system,
2
and the relative
paucity of agonists for this receptor, it was decided to
explore further the structure–activity requirements of 1.
An earlier paper by McKenna et al.
3
had compared a
variety of N-substituted tryptamines at both the 5-HT
1A
and 5-HT
2A/2C
receptors. We noted that the compound
with the greatest potency at the 5-HT
1A
receptor pos-
sessed the N,N-dialkyl substituents constrained into a
pyrrolidine ring. Thus, herein we describe the synthetic
route and the potent 5-HT
1A
agonist properties of 1-(4-
fluoro-5-methoxyindol-3-yl)pyrrolidine 2, as well as an
improved synthesis of its N,N-dimethyl congener. These
compounds, although somewhat less readily accessible
than the standard 5-HT
1A
receptor agonist, 8-hydroxy-
2-(N,N-dipropylamino)tetralin, are an order of magni-
tude more potent, thereby representing new pharmaco-
logical probes to study the functions of this receptor.
In our recent report,
1
we obtained compound 1 as a
minor product from the synthesis of 6-fluoro-5-meth-
oxy-N,N-dimethyltryptamine. Clearly, a more e=cient
approach was required, both for resynthesis of1, as well
as for preparation of any additional congeners such as
2. Our initial synthetic strategy was an attempt to func-
tionalize the 4-position of N
1
-TIPS-5-methoxy gramine
through lithiation and, with a few subsequent transfor-
mations, obtain the final product.
4
This methodology
failed because attempted lithiation at the 4-position
only afforded product where the triisopropylsilyl group
had rearranged from N
1
to C
2
. The successful approach
is shown below. Indole 5 was synthesized in high yield
via the Leimgruber–Batcho method,
5
converting the
corresponding toluene (3) to the styrene (4) followed by
catalytic reduction. Preparation of the bisulfite adduct,
followedby N-acetylation(6)allowedfortheintroduction
of bromine at the 5-position with concurrent removal of
the protecting groups (7).
6
A modification of the Ullmann
ether synthesis, employed earlier in our group,
7
was uti-
lized to displace the bromine with the methoxy function-
ality (8). It was necessary, however, to perform this
reaction under elevated pressure and temperature to
achieve a moderate yield. After chromatography, some
unreactedstartingmaterialmayberecoveredandrecycled.
Classical Speeter–Anthony tryptamine synthesis
8
leads to
the glyoxylamide (9) and with subsequent LAH reduction
thefinalproduct2wasobtained.Longrefluxtimesandthe
higher boiling dioxane are necessary for this reaction to
proceedtocompletion(Scheme1).
Table 1 shows the results of radioligand competition
studies at the 5-HT
1A
, 5-HT
2A
, and 5-HT
2C
serotonin
*Corresponding author. Tel.: +1-765-494-1461; fax: +1-765-494-
1414; e-mail: drdave@pharmacy.purdue.edu
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00062-2
794
U. Laban et al. /Bioorg. Med. Chem. Lett. 11 (2001) 793–795
receptor subtypes. Substitution of the dimethyl func-
tionality in 1 with a pyrrolidyl (2) results in a doubling
of 5-HT
1A
a=nity, as well as an increased selectivity for
5-HT
1A
/5-HT
2
binding. Compound 2 is more potent
than the standard 5-HT
1A
agonist 8-hydroxy-2-(N,N-
dipropylamino)tetralin (8-OH-DPAT) at this site and
has potency nearly comparable to the partial ergoline
LY293284.
9
An agonist effect at serotonin 5-HT
2A
sites
is believed responsible for the hallucinogenic proper-
ties
10
ofvarious drugs, while stimulationof 5-HT
1A
sites
results in anxiolytic effects.
2
The behavioral effects of drugs acting at 5-HT
1A/2A
receptors may be quantified using the two lever drug
discrimination procedure (DD).
11
In these experiments
we employed two hallucinogenic training drugs, LSD
and DOI (2,5-dimethoxy-4-iodoamphetamine),
1
and the
5-HT
1A
agonist LY293284.
1
Animals were trained on a
food-reinforced FR50 schedule. Drug discrimination
data for hallucinogen-like activity are shown in Tables 2
and 3. The fluorotryptamine 2 fails to substitute in
either LSD- or DOI-trained rats, consistent with its low
a=nity for 5-HT
2A
receptors, whereas in LY293284-
trained rats (Table 4) full substitution occurs at doses of
1 mmol/kg. This latter result is indicative of in vivo full
agonism of compound 2 at the serotonin 5-HT
1A
receptor subtype, an observation we have previously
made for compound 1.
1
Compound 2 (at 0.046mg/kg and higher) induced a
pronounced serotonin syndrome (i.e., flat body posture
and forepaw treading) that affected response rates,
causing behavioral disruption. These effects are char-
acteristic of agonist stimulation of the 5-HT
1A
receptor
in rats.
In conclusion, we have shown that 4-fluoro-5-methoxy-
tryptamines possess potent 5-HT
1A
activity. Although
compound 2 represents a further potency enhancement
over the N,N-dimethyl analogue 1, more potent con-
geners may exist. More importantly, general pharmaco-
logical studies of agonist effects at the 5-HT
1A
receptor
are almost exclusively carried out with the single agent
8-OH-DPAT. The new molecules reported herein offer
pharmacologists the opportunity to employ an agonist
from a different chemical class that possesses enhanced
potency and potentially enhanced selectivity. Further
characterization of compound2, particularly for a
=
nity
at other receptor types, is currently underway.
Scheme 1. (a) (CH
3
)
2
NCH(OCH
3
)
2
, pyrrolidine, DMF, reflux 3h,
77%; (b) H
2
, Pd/C, 84%; (c) (i) NaHSO
3
, rt, 24h; (ii) Ac
2
O, 3h, reflux
50%; (d) (i) Br
2
,H
2
O, 0
C; (ii) 5N aq NaOH, 75%; (e) NaOMe, CuI,
CH
3
CO
2
Et, 5h, sealed tube, 140
C, 70%; (f) (i) (CO)
2
Cl
2
,Et
2
O, 0.5h,
0
C; (ii) pyrrolidine, 24h, rt, 72%. (g) LAH, dioxane, 24h, 90
C,
69%.
Table 1. Results of radioligand competition studies at [
125
I] DOI-
labeled cloned rat 5-HT
2A
, rat 5-HT
2C
, and [
3
H]8-OH-DPAT-labeled
human 5-HT
1A
receptors (K
i
values
SEM in nanomolar)
Table3. Data from substitution tests in DOI-trained rats
Compd
5-HT
2A
a
5-HT
2C
5-HT
1A
Drug
Dose
mmol/kg
N
% D
% SDL
ED
50
(95% C.I.)
mmol/kg
1
122
14.2
55
9.4
0.23
0.03
2
130
3.2
140
8.4
0.12
0.012
0.83
0.093
b
DOI
10
0.29
(0.19–0.43)
8-OH DPAT
LY293284
0.053
0.012
2
0.125
9
22
0
a
Values are means of three experiments, standard deviation is given in
parentheses.
b
K
D
value.
0.25
10
30
29
N.S.
0.50
9
50
50
Table4. Data from substitution tests in LY293284-trained rats
Table2. Data from substitution tests in LSD-trained rats
Drug
Dose
mmol/kg
N % D % SDL ED
50
(95% C.I.)
mmol/kg
Drug
Dose
mmol/kg
N
a
%D
b
% SDL
c
ED
50
(95% C.I.)
mmol/kg
LY293284
10
0.031
(0.02–0.05)
LSD
15
0.026 (0.014–0.045)
2
0.125
10
10
11
8-OH-DPAT
10
0.099
(0.06–0.20)
0.25
15
53
57
N.S.
d
0.5
10
60
75
2
0.063
8
0
25
1.0
9
78
67
0.125
10 10
66.6
0.091
a
0.250
8 12.5
100
(0.064–0.12)
a
Number of animals tested at each dose.
b
Percentage of animals that failed to emit 50 responses within 5 min.
c
Percentage of animals tested that selected the training drug appro-
priate lever.
d
No substitution occurred.
0.50
9 66.6
100
1.0
10 90
100
a
Only the three lower doses were used to calculate the ED
50
because
the higher doses produced greater than 50% disruption of responding.
U. Laban et al. /Bioorg. Med. Chem. Lett. 11 (2001) 793–795
795
Acknowledgements
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The authors are grateful to Mr. Stewart Frescas for
many helpful suggestions. This work was supported by
NIH grant DA02189.
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