Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for neuronal nicotinic acetylcholine receptors

Article abstract of DOI:10.1016/j.bmcl.2008.10.002

Α series of novel 3,6-diazabicyclo[3.1.1]heptane derivatives 4a-f was synthesized and their affinity and selectivity towards α4β2 and α7 nAChR subtypes were evaluated. The results of the current study revealed a number of compounds (4a, 4b and 4c) having a very high affinity for α4β2 (K_i at α4β2 ranging from 0.023 to 0.056 nM) versus α7 nAChR subtypes; among these compounds, the 3-(6-bromopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane 4c was found to be the most α7α4β2 selective term in receptor binding assays (α7α4β2 = 1295). Moreover, compound 4d also had high affinity for the α4β2 nAChR subtype (K_i = 1.2 nM) with considerably high selectivity (α7/α4β2 = 23300).

Full text of DOI:10.1016/j.bmcl.2008.10.002

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6147–6150
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for neuronal
nicotinic acetylcholine receptors
a
a
b
c
Gabriele Murineddu a, , Caterina Murruzzu , Maria M. Curzu , Giorgio Chelucci , Cecilia Gotti ,
*
Annalisa Gaimarri c, Laura Legnani d, Lucio Toma d, Gerard A. Pinna a
a Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy
b Dipartimento di Chimica, Università di Sassari, via Vienna 2, 07100 Sassari, Italy
c CNR, Istituto di Neuroscienze, Farmacologia Cellulare e Molecolare, Dipartimento di Farmacologia Medica, Università di Milano, via Vanvitelli 32, 20129 Milano, Italy
d Dipartimento di Chimica Organica, Università di Pavia, via Taramelli 10, 27100 Pavia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
F series of novel 3,6-diazabicyclo[3.1.1]heptane derivatives 4a–f was synthesized and their affinity and
Received 10 September 2008
Revised 30 September 2008
Accepted 2 October 2008
Available online 5 October 2008
selectivity towards
revealed a number of compounds (4a, 4b and 4c) having a very high affinity for
from 0.023 to 0.056 nM) versus 7 nAChR subtypes; among these compounds, the 3-(6-bromopyridin-3-
yl)-3,6-diazabicyclo[3.1.1]heptane 4c was found to be the most 4b2 selective term in receptor bind-
ing assays ( 4b2 = 1295). Moreover, compound 4d also had high affinity for the 4b2 nAChR subtype
(Ki = 1.2 nM) with considerably high selectivity ( 7/ 4b2 = 23300).
Ó 2008 Elsevier Ltd. All rights reserved.
a
4b2 and
a
7 nAChR subtypes were evaluated. The results of the current study
a
4b2 (Ki at 4b2 ranging
a
a
a7a
a
7
a
a
Keywords:
a
a
3,6-Diazabicyclo[3.1.1]heptanes
Neuronal nicotinic acetylcholine receptors
Binding affinity
Modeling
Inflammatory disease and neuropathic insults are often accom-
panied by severe pain states (physiological, inflammatory, and
neuropathic) that can be treated with commonly prescribed anal-
gesic agents, such as non-steroidal anti-inflammatory drugs (NSA-
IDs) and opioids.1 Unfortunately, the therapeutic potential of these
powerful drugs has been limited by safety concerns, as well as by
unpleasant side effects with consequent poor patient compli-
ance.2–5
nAChR subunits form a plethora of different receptor subtypes
among which the most abundant in the CNS are the
4b2* and
the
7* receptors (the asterisks indicate the potential presence of
a
a
other subunits), whereas the
a3b4 receptor is the predominant
subtype at ganglionic synapses.11,12
The neuronal nAChRs are involved in a wide range of physiolog-
ical and pathophysiological processes, and they have been pro-
posed as potential therapeutic targets in
a
number of
Thus, the treatment of various form of pain is a hugely unmet
medical need, and the search for novel and efficacious analgesics
with improved therapeutic index receives considerable attention.6,7
Among a number of novel approaches to pain relief currently
under investigation, nicotinic acetylcholine receptors (nAChRs)
hold considerable potential as therapeutic targets for the develop-
ment of analgesic drugs.8,9 The neuronal nicotinic acethylcholine
receptors are prototypic ligand-gated ion channel receptors that
are widely expressed through the central and peripheral nervous
system and mediate fast synaptic transmission.8 Neuronal nAChRs
are pentameric proteins comprising either combinations of two
neurodegenerative and psychiatric disorders, in various form of
pain, and in nicotinic addiction.8,13–15
The
among academic and industrial researchers as a result of its role
in pain reflexes.16,17 Thus, the generation of potent
4b2 nAChR
a4b2 receptor subtype has generated significant interest
a
subtype selective ligands has been a goal for the advancement of
novel nAChR-based analgesics with a minimum of side effects.9
The alkaloid epibatidine (1), the exo-2-(6-chloropyridin-3-yl)-7-
azabicyclo[2.2.1]heptane, isolated from the skin of the ecuadorian
poison frog Epidobates tricolour,18 was identified as a potent ligand
of
a4b2 receptors having powerful analgesic activity.
different types of subunit (
subunit symmetrically arranged around a central ion pore.10 Nine
different types of -subunit ( 10) and three kinds of b-sub-
units (b2ꢀb4) have been cloned and characterized. The multiple
a and b) or five copies of the same a
Because of the identification of various adverse effects of 1 on
CNS responses and respiratory, gastrointestinal and cardiovascular
function, synthetic modifications of its structure have been per-
formed in order to improve potency and selectivity while reducing
the toxicity.
a
a2ꢀa
These endeavors, based upon examination of the two key struc-
tural elements of 1, that is, the (i) azabicyclo amine moiety and the
* Corresponding author.
E-mail address: muri@uniss.it (G. Murineddu).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.002

6148
G. Murineddu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6147–6150
(ii) pyridine heterocycle, led to a number of promising substances,
many of them closely related but also not related to epibatidine.
For example, tebanicline (2) described as an azetidine bioisoster
of 1 with (R)-absolute configuration, retained a potent nAChR
iridazine in toluene and in the presence of TEA. Treatment of 7a–e
with HCOOH underwent smooth deprotection of the Boc group lead-
ing to 4a–e in good-to-excellent yields (63–95%). Reaction of 4a with
HCOOH/HCHO produced the N6-methylderivative 4f in 72% yield.
The goal of this study was to prepare a series of 3,6-diazabicy-
agonism with moderate enhancement of
a4b2 nAChR subtype
selectivity as compared with 1. Tebanicline showed analgesic ac-
tion in a spectrum of acute and chronic nociceptive models as well
as in neuropathic pain but with only a modest therapeutic in-
dex.19–22
clo[3.1.1]heptane analogues of the
(6-chloropyridin-3-yl)-2,5-diazabicycloheptane,23 and to measure
their affinity at 4b2 and 7 nAChR subtypes. The strategy of
a4b2 nAChR subtype ligand, 2-
a
a
incorporating a novel diazabicycloheptane unit into the structure
Attempts to circumvent these problems induced W.H. Brunelle
and coworkers to synthesize a series of N-(3-pyridinyl)-bridged
bicyclic diamine derivatives as novel bridged nicotinoid, of which
of 3 was expected to afford compounds with high affinity for
a
4b2 nAChR subtype. Modifications were principally made on
the pyridine ring to investigate the effect of different variations
on 4b2 and 7 nAChR subtype potency and selectivity.
Binding assays were performed on rat cortex tissues for
2-(6-chloropyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane (3) is
a
a
a
representative term exhibiting exceptionally potent affinity for
a
4b2
the
a
4b2 receptors but, unfortunately, inadequate pharmacokinetic
and a a -bunga-
7 nAChR subtypes with [3H]-epibatidine and [125I]-
properties (poor CNS penetration).23 As a consequence compound 3
was not selected as a candidate for clinical evaluation. Neverthe-
less, the diazabcycle 3 could be assumed as a lead compound for
rotoxin as radioligands, respectively.25,26 The binding affinities (Ki
values) for the new ligands,27 as well as the reference compounds
3 and radioligands at
a4b2 and a7 nAChR subtypes are shown in
the design of novel high-affinity
a4b2 subtype-selective ligands.
Table 1.
In this context, the aim of this study was to investigate the ef-
fect of the variation of the 2,5-diazabicyclo[2.2.1]heptane scaffold
of 3 with the 3,6-diazabicyclo[3.1.1]heptane skeleton synthesizing
a range of isomers and analogues based on this diazabicyclic
framework. This paper describes the synthesis of compounds 4
In general, results showed a spectrum of
affinities ranging from 0.023 nM for compound 4a to 1.2 nM for
compound 4d, with 7 nAChR subtype affinities ranging from
1.36 nM for compound 4b to 28,000 for compound 4d. Thus, the
nAChR affinities of all of the investigated 3,6-diazabicy-
a4b2 nAChR subtype
a
a7
and the evaluation of their binding affinity at
subtypes (Fig. 1).
a4b2 and
a
7 nAChR
clo[3.1.1]heptanes are lower than their
affinities.
a4b2 nAChR subtype
The synthetic route to the desired final compounds 4 is outlined
in scheme 1. The sequence commenced with the addition of the
monoprotected 3,6-diazabicyclo[3.1.1]heptane 524 and haloazines
6 to a toluenic mixture of Pd-BINAP catalyst in the presence of a base
(Cs2CO3 or NaOtBu), resulting in coupling products 7a–d. Synthesis
ofcompound7ewasaccomplishedbyrefluxing5with3,6-dichorop-
Compound 4a, having a 3,6-diazabicyclo[3.1.1]heptane ring
replacing the 2,5-diazabicyclo[2.1.1]heptane ring of 3, had Ki val-
ues of 0.023 nM and 4.1 nM for
a4b2 and a7 nAChR subtype,
respectively, with a 7: 4b2 selectivity ratio of 178. Compound
a
a
4a serves as a convenient benchmark for all of the others in term
of presenting structure-binding affinity relationships.
H
Cl
N
Table 1
N
H
O
Cl
N
Binding affinity (Ki, nM)a of 4a–f to
a
4b2 and
a
7 nAChR subtypes.
7: [125
-BgTx] Selectivity Ki
N
Compound
a
4b2: [3H-Epibatidine]
a
a
(Epibatidine)
1
2 (Tebanicline)
(Ki, nM)
(Ki, nM)
ratio a7/a4b2
4a
4b
4c
4d
4e
4f
3
0.023 (34%)
0.056 (28%)
0.039 (36%)
1.2 (45%)
0.168 (33%)
0.43 (34%)
0.018b
4.1 (35%)
1.36 (42%)
50.5 (46%)
28000 (52%)
25 (48%)
20 (42%)
—
178
24.3
1295
23300
149
46.5
—
Z
Cl
N
Y
N
N
N
N
HN
X
4
3
X = H, Y = CH, Z = Cl ( )
a
3H-Epibatidine
0.083
—
0.8
0.9
9.6
—
X = H, Y = CH, Z =H ( )
b
125I-
a
-Bungarotoxin
X = H, Y = CH, Z = Br ( )
c
2
X = H, Y = CH, Z = NO ( )
d
a
The Ki values shown were the mean (% coefficient of variation) of three inde-
X = H, Y = N, Z = Cl ( )
e
pendent measurements.
X = CH , Y = CH, Z = Cl ( )
f
3
b
Binding affinity of compound 323 was determined by the inhibition of [3H]
cytosine binding in homogenates of rat striatum.
Figure 1. Epibatidine and related analogues.
Z
Z
Z
NH
i
ii
N
N
+
N
Y
N
Y
N
N
O
X
Y
N
N
O
O
5
X
6
7a-e
4
O
X = H, Y = CH, Z = Cl ( ) (81%)
X = I, Y = CH, Z = Cl (a)
a
b
X = H, Y = CH, Z =H ( ) (81%)
b
X = I, Y = CH, Z = H ( )
X = I, Y = CH, Z = Br (c)
X = I, Y = CH, Z = NO2 (d)
X = Cl, Y = N, Z = Cl (e)
X = H, Y = CH, Z = Br ( ) (95%)
c
iii
X = H, Y = CH, Z = NO ( ) (81%)
d
2
X = H, Y = N, Z = Cl ( )
(63%)
e
X = CH , Y = CH, Z = Cl ( ) (72%)
f
3
Scheme 1. Reagents and conditions: (i) Pd2(dba)3, rac-BINAP, Cs2CO3 or NaOtBu, toluene, 100–110 °C, 22 h (for compounds 7a–d); TEA, toluene, 120 °C, 24 h (for compound
7e); (ii) HCOOH 99%, rt, 3.5 h; (iii) HCOOH 99%/HCHO 40%, 110 °C, 2.5 h.

G. Murineddu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6147–6150
6149
De-chloro compound 4b displayed 2.4-fold lower
a
4b2 nAChR
nitrogen and the pyridine nitrogen (A–B distance) or the center
of the pyridine ring (A–C distance). The data in Table 2 and the
three-dimensional plots, represented in Figure 2, show the very
close similarity between 3 and 4a that can justify the almost iden-
subtype affinity than 4a whereas the 7 nAChR subtype affinity
a
was increased displaying 3-fold greater affinity.
The bromo-substituted compound 4c had 1.7-fold and 12.3-fold
lower affinity than 4a for
a selectivity ratio of 1295.
Substitution with a nitro group, compound 4d, resulted in a
reduction, about 52-fold, of 4b2 receptor affinity and a much
7 receptor affinity with the highest selectivity
a
4b2 and
a
7, respectively, and possessed
tical binding affinity to a4b2 nAChR. In fact, each conformation of
4a shows energy and geometry data in strict analogy with the cor-
responding conformation of 3. Moreover, in all the conformations
the orientation of the chloropyridinyl group allows a good conjuga-
a
higher reduction of
ratio (23300).
a
tion with the adjacent nitrogen atom (
It is worthy pointing out that both compounds show A–B distances
s
2 always about 90 or ꢀ90°).
These results indicate that factors such as electronics are likely
involved in the binding of 4a analogues.
of about 6 Å and A–C distances of 5.0–5.5 Å confirming that these
long distances are compatible with affinity for
the subnanomolar range.31
a4b2 receptors in
Without doubts, the incorporation of a chlorine atom at C60 po-
sition of the pyridine moiety as in 4a is favourable for
a
4b2 affinity.
The conformational behavior of 4b–f, not reported in Table 2,
are very similar to those of 4a. Thus, modulation of activity exerted
by the substituent at C60 (4b–d), the second nitrogen in the aro-
matic ring (4e), or the N6-methyl substitution (4f) seems to derive
from specific interactions of these groups rather than from their
influence on the conformation of the molecules.
Compound 4e has two basic nitrogen in the heteroaryl aromatic
ring and is more hydrophilic than compound 4a. This pyridazine
derivative 4e had 7.3-fold and 6.1-fold lower affinity than 4a for
a
4b2 and
N6-Methyl substitution of 4a as in compound 4f lowered affin-
ities for both receptors with Ki values of 0.43 nM for 4b2 receptor
and of 20 nM for 7 receptor.
The best compounds in the 4a–f series show affinity for
a7 nACh receptor subtypes, respectively.
a
a
a
4b2
nAChR in the same range as their diazabicyclo[2.2.1]heptane ana-
logue 3 suggesting similar geometrical and conformational proper-
ties. Thus, we performed a modeling study on the protonated form
of these compounds through optimizations within the density
functional approach at the B3LYP/6-311+G(d,p) level.28 The energy
of the optimized structures were recalculated using a continuum
solvent model (PCM)29 as implemented in Gaussian 0330 to take
into account the effect of water on these highly polar molecules.
The main degree of conformational freedom of compounds 3 and
4 is the rotation of the aryl group around the single bond that con-
nects it to the diazabicyclic system. This rotation cannot be ex-
pected to be completely free as the orientation of the aromatic
ring can be influenced by the resonance with the lone pair of the
nitrogen atom to which it is connected, so that conformations that
make possible this conjugation should be preferred. This nitrogen
atom usually does not assume a completely planar geometry but
shows a certain degree of pyramidalization that originates two
possible ‘configurations’. Finally, in 4 the piperazine ring can, in
principle, assume either a chair or a boat conformation contrarily
to 3 where the same ring is forced into a twisted boat geometry.
Several minimum energy conformations were located for each
compound and in Table 2 are reported the gas-phase and the
water-solvated energies of 3 and 4a together with selected geo-
metrical features including the distance between the protonated
Figure 2. 3D plot of the most representative conformations of compounds 3 and 4a.
Table 2
Relative energy and selected geometrical data of the B3LYP/6-311+G(d,p) calculated minimum energy conformations of compounds 3 and 4a.a
Conformation
Erel (gas-phase) (kcal/mol)
Erel (water) (kcal/mol)
A–Bb(Å)
A–Cc(Å)
s1d(°)
s2e(°)
af (°)
3A
3B
3C
3D
4aA
4aBg
4aC
4aDh
0.34
0.00
1.28
1.18
0.02
0.02
0.00
0.00
0.00
0.05
1.09
1.13
0.00
0.00
1.42
1.42
5.78
5.67
6.31
6.24
6.29
6.29
6.14
6.14
5.00
4.98
5.48
5.46
5.49
5.49
5.32
5.32
ꢀ21
154
8
ꢀ94
81
8.8
8.9
ꢀ5.9
ꢀ4.5
3.1
ꢀ100
ꢀ177
75
ꢀ9
ꢀ88
88
169
11
3.1
ꢀ91
ꢀ4.6
ꢀ167
91
ꢀ4.6
a
Several other minimum energy conformation were located for 4a, but they are not reported as their water-solvated energy is 5–7 kcal/mol higher than that of 4aA.
Distance between the protonated nitrogen and the pyridine nitrogen.
b
c
d
e
f
Distance between the protonated nitrogen and the center of the pyridine ring.
s1 is C3–N2–C30–C20 for 3 and C2–N3–C30–C20 for 4a.
s2 is the inproper torsional angle N+–N2–C30–C20 for 3 and N+–N3–C30–C20 for 4a.
Pyramidalization degree of the nitrogen atom bearing the aryl substituent defined as the difference between 360 and the sum of the three bond angles of the same atom,
considered positive when it is pyramidalized in the direction of the methylene bridge and negative in the opposite case.
g
Conformation enantiomeric to 4aA.
Conformation enantiomeric to 4aC.
h

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G. Murineddu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6147–6150
Puttfarcken, P.; Searle, X.; Ji, J.; Putman, C. B.; Surowy, C.; Toma, L.; Barlocco, D.
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Cignarella, G.; Pinna, G. A. Bioorg. Med. Chem. 2006, 14, 676.
25. Dellanoce, C.; Bazza, C.; Grazioso, G.; De Amici, M.; Gotti, C.; Riganti, L.;
Clementi, F.; De Micheli, C. Eur. J. Org. Chem. 2006, 3746.
26. Gotti, C.; Balestra, B.; Moretti, M.; Rovati, G. E.; Maggi, L.; Rossoni, G.; Berti, F.;
Villa, L.; Pallavicini, M.; Clementi, F. Br. J. Pharmacol. 1984, 124, 1197.
27. Munson, P. J.; Rodbard, D. Anal. Biochem. 1980, 107, 220.
In summary, we have prepared ligands for a4b2 and a7 nAChR
subtypes that combines a 3,6-diazabicyclo[3.1.1]heptane core with
various pyridines and a pyridazine. Most of these ligands have very
high affinity for
has a chloropyridine motif and binds 3.6 times better than epibati-
dine to 4b2 nAChR subtypes in the meantime maintaining similar
4b2 affinity respect to the lead 3.
a
4b2 nAChR subtypes. The best, compound 4a,32
a
a
28. Becke, A. D. J. Chem. Phys. 1993, 98, 5648; Lee, C.; Yang, W.; Parr, R. G. Phys. Rev.
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10.1 mmol) were mixed with an additional amount of toluene (10 mL). Then,
the Pd(OAc)2/BINAP solution was added and the mixture was refluxed for 22 h.
After cooling, the residue was partitioned between diethyl ether and water.
The organic phase was washed with water, dried (Na2SO4) and evaporated. The
resulting crude product was purified by flash column chromatography
(petroleum ether/Ethyl acetate 7:3) to give 7a as a yellow solid (66%). Rf:
0.29; mp = 129–130 °C; 1H NMR (200 MHz, CDCl3, d/ppm): 1.35 (s, 9H), 1.51 (d,
1H, J = 8.8 Hz); 2.58–2.78 (m, 1H); 3.26 (d, 2H, J = 10.6 Hz), 3.82–3.95 (m, 2H);
4.30 (d, 2H, J = 10.4 Hz) 6.97 (dd, 1H, J = 3.0 and 8.8 Hz); 7.17 (d, 1H, J = 8.8 Hz),
7.86 (d, 1H, J = 3.0 Hz). Anal. Calcd for C15H20ClN3O2: C, 58.16; H, 6.51; N, 18.56.
Found: C, 58.20; H 6.40; N 18.60.A solution of 7a (0.28 g, 0.90 mmol) in HCOOH
99% (5 ml) was stirred at room temperature for 3.5 h. The mixture was diluted
with water and K2CO3 was added until neutral pH. The solution was extracted
with CH2Cl2 dried (Na2SO4) and evaporated. The residue was triturated with
diethyl ether to give the final compound 4a as a white solid (81%). Rf: 0.21
(CH2Cl2/methanol 7:3); mp = 130–131 °C; 1H NMR (200 MHz, CDCl3, d/ppm):
1.53 (br s, 1H), 1.62 (d, 1H, J = 8.8 Hz); 2.70–2.85 (m, 1H); 3.48–3.55 (m, 4H),
3.88–3.95 (m, 2H); 6.97 (dd, 1H, J = 2.8 and 8.8 Hz); 7.18 (d, 1H, J = 8.2 Hz), 7.87
(d, 1H, J = 3.2 Hz). Anal. Calcd for C10H12ClN3: C, 57.28; H, 5.77; N, 20.04.
Found: C, 57.16; H 5.74; N 19.90.
23. Bunnelle, W. H.; Daanen, J. F.; Ryther, K. B.; Schrimpf, M. R.; Dart, M. J.; Gelain,
A.; Meyer, M. D.; Frost, J. M.; Anderson, D. J.; Buckley, M.; Curzon, P.; Cao, Y. J.;