Carbamoylcholine analogs as nicotinic acetylcholine receptor agonists-Structural modifications of 3-(dimethylamino)butyl dimethylcarbamate (DMABC)

Article abstract of DOI:10.1016/j.bmcl.2008.11.011

Compounds based on the 3-(dimethylamino)butyl dimethylcarbamate (DMABC) scaffold were synthesized and pharmacologically characterized at the α₄β₂, α₃β_4, α₄β₄ and α₇ neuronal nicotinic acetylcholine receptors (nAChRs). The carbamate functionality and a small hydrophobic substituent in the C-3 position were found to be vital for the binding affinity to the nAChRs, whereas the carbamate nitrogen substituents were important for nAChR subtype selectivity. Finally, the compounds were found to be agonists at the α₃β₄ nAChR.

Full text of DOI:10.1016/j.bmcl.2008.11.011

Bioorganic & Medicinal Chemistry Letters 19 (2009) 87–91
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Carbamoylcholine analogs as nicotinic acetylcholine receptor
agonists—Structural modifications of 3-(dimethylamino)butyl
dimethylcarbamate (DMABC)
*
Camilla P. Hansen, Anders A. Jensen , Thomas Balle, Klaus Bitsch-Jensen,
*
Mohamud M. Hassan, Tommy Liljefors, Bente Frølund
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Copenhagen University, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
Compounds based on the 3-(dimethylamino)butyl dimethylcarbamate (DMABC) scaffold were synthe-
Received 1 October 2008
Revised 1 November 2008
Accepted 4 November 2008
Available online 7 November 2008
sized and pharmacologically characterized at the a4b2, a3b4, a4b4 and a7 neuronal nicotinic acetylcholine
receptors (nAChRs). The carbamate functionality and a small hydrophobic substituent in the C-3 position
were found to be vital for the binding affinity to the nAChRs, whereas the carbamate nitrogen substitu-
ents were important for nAChR subtype selectivity. Finally, the compounds were found to be agonists at
the a3b4 nAChR.
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Carbamoylcholine (CCh)
Nicotinic acetylcholine receptors agonists
a4b2 nAChR
3-(Dimethylamino) butyl
dimethylcarbamate
The nicotinic acetylcholine receptors (nAChRs) are ligand-gated
ion channels mediating the effects of the neurotransmitter acetyl-
choline (ACh).1–4 In addition to mediating the fast synaptic re-
sponse of ACh in postsynaptic terminals, presynaptic nAChRs
regulate the activities in the cholinergic synapse and in other
important neurotransmitter systems.5–8 Hence, the receptors are
involved in various physiological processes and are implicated in
a wide range of neurodegenerative and psychiatric disorders, for
example, schizophrenia, depression, epilepsy, Alzheimer’s disease
and Parkinson’s disease. Furthermore, the nAChRs are important
targets in smoking cessation.9–15
a7 nAChRs in binding assays.16–18 Compound 3 was of particular
interest as it was found to be a fairly potent partial
a4b2 agonist
with negligible activities at the 3b4 and the 7 nAChRs when stud-
a
a
ied at these receptors expressed in Xenopus oocytes, using the two
electrode voltage clamp technique.17 Our structure–activity rela-
tionship (SAR) studies of the DMABC scaffold have so far led to
the following major conclusions: (1) A tertiary amino group and
one small hydrophobic substituent (such as methyl or ethyl) in
the C-3 position are key determinants for high-affinity binding to
the nAChRs16,18 and (2) the nature of the carbamate nitrogen sub-
stituents greatly affects the nAChR binding affinities and a4b2/a3b4
The nAChRs are pentameric assemblies of subunits, which are
either heteromeric complexes (composed of a2–6 and b2–4 or a9
selectivities of the DMABC analogs.16–18 More specifically, intro-
duction of azetidine rings at the carbamate nitrogen has resulted
and
a10) or homomeric complexes (
a7 or
a9). The
a
4b2* (the aster-
in highly a4b2 selective compounds displaying nanomolar binding
isk indicates the possible presence of other subtypes) and the a7
affinities to this receptor, whereas introduction of substituents lar-
ger than that (e.g. pyrrolidine, N,N-diphenyl and N,N-dipropyl) has
led to diminished binding affinities to all nAChRs.16–18 Smaller sub-
stituents at the carbamate nitrogen are well tolerated, yet they re-
nAChRs are the major CNS subtypes, whereas the
ganglionic nAChR.2
a
3b4* is the major
Previously, we have reported the synthesis and pharmacological
characterization of several series of carbamoylcholine derived li-
gands based on the 3-(dimethylamino)butyl dimethylcarbamate
(DMABC, 1, Fig. 1) scaffold.16–18 Several of these compounds,
including compounds 1–4 (Fig. 1), were nAChR agonists with pro-
sult in compounds with decreased
a4b2 nAChR selectivity
compared to those of 3 and 4.16–18 Similar trends were found in
a series of DMABC derived esters, where the carbamate nitrogen
was replaced by a methine group.17 However, the decrease in affin-
ity as a result of increasing substituent size, was more pronounced
in the ester series than in the carbamate series. The difference was
attributed to the sp3 hybridization of the methine carbon causing a
slightly different spatial orientation of the substituents as com-
pared to the sp2 hybridized carbamate nitrogen.17
nounced selectivities to the
a4b2 subtype over b4-containing and
* Corresponding authors. Tel.: +45 35336491; fax: +45 35336040 (A.A.J.); tel.:
+45 35336494; fax: +45 35336040 (B.F.).
E-mail addresses: aaj@farma.ku.dk (A.A. Jensen), bfr@farma.ku.dk (B. Frølund).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.11.011

88
C. P. Hansen et al. / Bioorg. Med. Chem. Lett. 19 (2009) 87–91
Figure 1. Acetylcholine (ACh), carbamoylcholine (CCh) and examples of the DMABC series, compounds 1, 2, 3 and 4.
In the present study, we thoroughly probe the carbamate func-
tionality of the DMABC scaffold (5–10, Fig. 2) and continue to ex-
plore the SARs of the C-3 position by substitution of the methyl
group with small or planar substituents (11a–d, Fig. 2). Further-
more, we present a series of carbamate N-substituted DMABC ana-
logs (12a–e, Fig. 2), as homology modeling studies revealed a
rather spacious area in the binding pocket possibly allowing the
introduction of larger substituents in one of the carbamate nitro-
gen positions while keeping one methyl group (Fig. 3).
Finally, we report a series of analogs with one hydrogen substi-
tuent on the carbamate nitrogen in order to further investigate the
a4b2/
a
3b4 selectivity exhibited by compound 2 (13a–e, Fig. 2).16,18
Compound 5 was synthesized from 5-oxohexanoic acid by
amidation followed by reductive amination, whereas 6a–b
were formed in Horner–Wadsworth–Emmons reactions from 3-
dimethylamino-butan-1-ol.19 Compounds 7, 12a,b,e and 13a–e
were synthesized according to standard carbamate formation pro-
cedures16–18,20 from 3-dimethylamino-butan-1-ol and the appro-
priate thiocarbamoyl chloride, amine, carbamoyl chloride or
isocyanate. Similar procedures were employed to obtain com-
pounds 8 and 11a–d using the appropriately 3-substituted ami-
nothiol or aminoalcohols and dimethylcarbamoyl chloride.
Compounds 12c–d were formed in palladium cross coupling reac-
tions of 2 and the arylchloride21,22, while the ureas 9 and 10 were
synthesized from 4-oxopentanoic acid using a modified Curtius
reaction with diphenyl phosphorazidate (DPPA) and the appropri-
ate amine followed by reductive amination.23 All new compounds
were characterized by 1H NMR, 13C NMR and CHN analysis.
The nAChR binding properties of compounds 5–13e were deter-
Figure 3. Compound 1 docked in the binding pocket of the homology model of the
4b2 receptor.17,32 The displayed PASS33-contour shows the cavities in the protein
structure. A red color signifies deep burial in the protein whereas the blue area is
closer to the surface.
a
and
[3H]MLA binding assay to tsA-201 cells transiently expressing the
7/5-HT3A chimera.17 The functional properties of the compounds
a4b4 nAChRs stably expressed in HEK293 cells and in a
mined in a [3H]epibatidine binding assay to heteromeric
a4b2, a3b4
a
Figure 2. The newly synthesized DMABC analogs cPx, cyclopropyl; Bn, benzyl.

C. P. Hansen et al. / Bioorg. Med. Chem. Lett. 19 (2009) 87–91
89
at the
a
3b4 nAChR-HEK 293 cell line were determined in the FLIPR
gen is critical for binding and support the existence of a water-
mediated hydrogen bond in this region of the binding pocket.17,26
Replacement of the ether-like oxygen in 1 with methylene,
methine, sulfur or nitrogen (giving compounds 5, 6b, 8 and 9,
respectively) also resulted in ligands with significantly impaired
binding affinities to all heteromeric nAChRs (Table 1). The ob-
served decreases in binding affinity likely arise from several fac-
tors. Firstly, the hydrogen bonding properties of the carbonyl
group are essential, as observed for compound 7, and these will
be affected by substitutions of the neighboring oxygen atom. Sec-
ondly, the degree of flexibility in the carbon chain is important.
Compounds 5, 6b, 8 and 9 are all more rotationally restricted than
1, which most likely affects the ability of the compounds to adopt
the bioactive conformations. Thirdly, the most detrimental de-
crease in binding affinity compared to compound 1 was observed
for urea 9. This may partly be explained by the cost of desolvating
the NH group of 9 in the absence of compensatory hydrogen bond-
ing partners in the receptor.
The binding affinities displayed by compounds 11a–11d were in
concordance with observations made for previous C-3 substituted
analogs.16 Introduction of aromatic groups in the C-3 position
(compounds 11c and 11d) led to decreased binding affinities to
all heteromeric nAChRs compared to 1, and although these ring
systems were planar, the effect of aromatic substitution was com-
parable to the effect of a previously reported cyclohexyl substitu-
ent.16 Analogously, the cyclopropyl analog (11b) displayed
similar binding affinities to the nAChRs as the isopropyl analog.16
Interestingly, introducing a hydroxymethyl group in the C-3
Membrane PotentialTM (FMP) assay.17 The pharmacological experi-
ments were conducted as described in the literature.17 The binding
affinities of compounds 1, 5–13e to the
and to the 7/5-HT3A chimera are given in Table 1. The functional
characteristics of these compounds at the 3b4 nAChR are given
a4b2, a3b4 and a4b4 nAChRs
a
a
in Table 2 together with those of acetylcholine and compound 2.
The observed pharmacological profiles of compounds 5–13e at
the heteromeric nAChRs exhibit similar trends when grouping
the compounds according to their structural resemblance, that is
as non-carbamates (5–10), carbamates with C-3 carbon substitu-
tions (11a–d) and carbamates with carbamate nitrogen substitu-
tions (12a–13e). In the following, the SARs are thus discussed
within these groups unless specifically mentioned below. None of
the compounds displayed significant affinity for the homomeric
a7 receptor which is in agreement with all previously synthesized
compounds in the DMABC series.16–18
Exchanging the carbonyl oxygen of 1 with a sulfur atom (com-
pound 7) had detrimental effects on the binding affinity to all het-
eromeric nAChRs (Table 1). A similar effect has been observed for
cytisine and thiocytisine, where the latter exhibited a 7- and 15-
fold reduction in binding affinity to the
a4b2 and the a7 nAChRs,
respectively, compared to cytisine.24 Sulfur is not as electronega-
tive as oxygen and in addition, the optimal direction and length
of hydrogen bonding to sulfur differ from those of hydrogen bond-
ing to oxygen.25 The decreased nAChR binding affinity of com-
pound 7 and thiocytisine, compared to 1 and cytisine, thus
indicate that the hydrogen bonding properties of the carbonyl oxy-
Table 1
Binding characteristics of the DMABC analogs at stable HEK293 cell lines expressing rat
chimera
a4b2, a3b4, and a4b4 nAChRs and at tsA201 cells transiently expressing the a7/5HT3A
Compound
a4b2
a3b4
a
4b4
a7/5YN3F
Compound
a4b2
a
3b4
a4b4
a7/5YN3F
1a
5
6a
6b
7
8
9
10
11a
11b
11c
0.02 [7.7 0.04]
1.1 [5.0 0.05]
6.6 [5.2 0.05]
0.29 [6.5 0.04]
1.5 [5.8 0.05]
1.6 [5.8 0.03]
ꢀ100 [ꢀ4]
0.42 [6.4 0.06]
ꢀ300 [ꢀ3.5]
24 [4.6 0.05]
6.3 [5.2 0.06]
4.9 [5.3 0.04]
ꢀ100 [ꢀ4]
0.15 [6.8 0.04]
72 [4.1 0.02]
4.6 [5.3 0.01]
2.5 [5.6 0.02]
6.9 [5.2 0.05]
19 [4.7 0.04]
ꢀ100 [ꢀ4]
>1000 [<3]
>1000 [<3]
>1000 [<3]
>1000 [<3]
>1000 [<3]
>1000 [<3]
>1000 [<3]
>1000 [<3]
>1000 [<3]
>1000 [<3]
ꢀ1000 [ꢀ3]
11d
12a
12b
12c
12d
12e
13a
13b
13c
13d
13e
35 [4.5 0.04]
1.6 [5.8 0.05]
9.8 [5.0 0.03]
12 [4.9 0.03]
23 [4.6 0.04]
0.13 [6.9 0.05]
1.9 [5.7 0.06]
0.036 [7.4 0.05]
0.048 [7.3 0.05]
0.20 [6.7 0.06]
0.091 [7.0 0.04]
35 [4.5 0.05]
14 [4.8 0.04]
12 [4.9 0.03]
14 [4.9 0.04]
25 [4.6 0.03]
1.4 [5.8 0.05]
3.2[5.5 0.04]
12 [4.9 0.05]
4.9 [5.3 0.03]
2.2 [5.7 0.05]
38 [4.4 0.05]
6.6 [5.2 0.05]
3.9 [5.4 0.05]
3.4 [5.5 0.05]
3.9 [5.4 0.06]
9.5 [5.0 0.03]
0.42 [6.4 0.06]
2.1 [5.7 0.05]
0.79 [6.1 0.04]
1.6 [5.8 0.04]
8.1 [5.1 0.01]
1.4 [5.8 0.04]
ꢀ1000 [ꢀ3]
>1000 [<3]
ꢀ1000 [ꢀ3]
ꢀ1000 [ꢀ3]
ꢀ1000[ꢀ3]
ꢀ1000 [ꢀ3]
>1000 [<3]
>1000 [<3]
>1000 [<3]
>1000 [<3]
ꢀ1000 [ꢀ3]
ꢀ1000 [ꢀ3]
ꢀ300 [ꢀ3.5]
ꢀ1000 [ꢀ3]
ꢀ300 [ꢀ3.5]
3.6 [5.4 0.04]
6.5 [5.2 0.04]
41 [4.4 0.03]
ꢀ100 [ꢀ4]
18 [4.7 0.06]
3.8 [5.4 0.05]
3.2 [5.5 0.05]
40 [4.4 0.01]
45 [4.4 0.04]
The Ki values are given in
l
M with the pKi SEM values in brackets.
a
Binding data for compound 1 is from Ref. 17.
Table 2
Functional characteristics of the DMABC analogs at the stable
a3b4-HEK293 cell line in the FMP assay
Compound
TC50 [pEC50 SEM]
Rmax SEM
Compound
TC50 [pEC50 SEM]
Rmax SEM
ACh
1
19 [4.7 0.03]
12 [4.9 0.03]
170 [3.8 0.04]
>1000 [<3]
150 [3.8 0.05]
91 [4.0 0.04]
53 [4.3 0.04]
430 [3.4 0.03]
>3000 [<2.5]
>3000 [<2.5]
>3000 [<2.5]
>1000 [<3]
—
11ca
11da
12a
>1000 [<3]
>1000 [<3]
160 [3.8 0.05]
51 [4.3 0.04]
28 [4.5 0.04]
>1000 [<3]
n.d.
n.d.
82
37
22
n.d.
69
93
96
69
107
103
n.d.
96
89
67
5
5
2
5
4
5
5a
12b
12c
6a
6b
7
2
5
2
4
12da
12e
6.7 [5.2 0.03]
57 [4.2 0.03]
55 [4.3 0.04]
95 [4.0 0.02]
ꢀ300[ꢀ3.5]
5
3
4
3
8
31
13a
9b
n.d.
n.d.
n.d.
n.d.
13b
13c
10b
11ab
11ba
13dc
13ea
n.d.
n.d.
>1000 [<3]
The EC50 values are given in
lM (with the pEC50 SEM values in brackets), and the Rmax values are given in % of the Rmax of ACh.
n.d., not determined.
a
Significant agonist responses were observed at concentrations higher than 300
Significant agonist responses were observed at concentrations higher that 1 mM.
The EC50 value for this compound is an estimate.
l
M.
b
c

90
C. P. Hansen et al. / Bioorg. Med. Chem. Lett. 19 (2009) 87–91
position (11a) led to a 120- to 240-fold decrease in nAChR binding
affinity compared to 1, whereas the binding affinity of the corre-
sponding ethyl analog was much less affected (e.g. by a factor of
previous studies16–18 where bulkier C-3 substituents were
investigated.
Furthermore, the present study confirms that the carbamate
nitrogen substituents greatly affect the binding properties and sub-
type selectivities of the DMABC analogs. Compounds with small
hydrophobic substituents, whether they are mono- or disubsti-
tuted with, for example, methyl or ethyl groups, display nanomolar
7 at the a
4b2 nAChR).18 The two substituents are almost equivalent
in size which indicates that polar C-3 substituents are disfavored.
Introduction of aromatic groups like phenyl (12b), p-chloro-
phenyl (12c) and p-cyanophenyl (12d) at the carbamate nitrogen
of the DMABC scaffold gave rise to compounds with markedly de-
creased binding affinities to all heteromeric nAChRs as compared
to 1, which was convergent with earlier observations.16–18 How-
ever, unlike any other compounds in the DMABC series, com-
pounds 12b–d displayed a slight preference (2- to 3-fold) for the
binding affinities to the a4b2 nAChR in addition to exhibit marked
selectivities for this receptor. Hydrophilic carbamate nitrogen sub-
stituents, on the other hand, are unfavorable as are aromatic
groups directly attached to the carbamate nitrogen. However, the
binding properties of 12e and 13e suggest that larger groups (such
as for example aromatic groups) might be allowed as substituents
in one of the carbamate nitrogen positions, if they are attached to a
linker. The possibility of introducing a linker between two ligands
(making a bivalent ligand) or between a ligand and a receptor spe-
cific group (such as a larger hydrophobic group that recognizes a
hydrophobic pocket somewhere on the receptor) is intriguing
and has been explored by various groups in the nAChR system27,28
as well as other neurotransmitter systems.29–31 Thus, the linker ap-
proach will be an interesting path to pursue in future studies.
Finally, the DMABC analogs presented in this study were
a4b4 nAChR over the a4b2 subtype. Interestingly, the benzyl analog
12e had considerably higher binding affinities to all heteromeric
nAChRs compared to those of 12a–d. In particular, the compound
exhibited nanomolar binding to the
a4b2 nAChR which, together
with the nanomolar 4b2 binding affinity displayed by 13e, sug-
a
gests that the receptor has a narrow hydrophobic pocket extending
outwards from the orthosteric site. Hence, the spacious area, which
was observed in the homology modeling of the a4b2 nAChR (Fig. 3),
seems to be a little narrower than initially anticipated, and a ligand
might require a linker moiety between the carbamate nitrogen and
an aromatic group in order to accommodate this area of the
receptor.
shown to be agonists at the a3b4 nAChR like all other compounds
in the series to date.16–18 Based on the resemblance with com-
In the above-mentioned compounds both carbamate nitrogen
positions were substituted and only one analog with a mono
substituted carbamate (compound 2) has previously been synthe-
sized and analyzed. This compound displayed low nanomolar
pounds 3 and 4 which in previous studies exhibited agonistic
properties at the a4b2 nAChR, the reported analogs are most likely
agonists at this receptor as well, although this remains to be
determined.
binding affinity to the
a4b2 nAChR (Ki = 13 nM) and a high degree
of 4b2/
a
a
3b4 selectivity (770-fold).18 Replacement of the methyl
Acknowledgments
group at the carbamate nitrogen in 2 with ethyl or propyl groups
(analogs 13b and 13c), resulted in ligands with binding profiles
very similar to 2, although the compounds did not exhibit the
Drs. James W. Patrick and David J. Julius are thanked for provid-
ing the nAChR and 5-HT3A receptor cDNAs. Drs. Ken Kellar and
same level of
analog 13a and hydrophilic hydroxyethyl derivative 13d both dis-
played a decreased binding affinity to the 4b2 nAChR (Table 1).
a
4b2/
a
3b4 selectivity (Table 1). The unsubstituted
Yingxian Xiao are thanked for giving us the
cell lines and Dr. Joe Henry Steinbach for providing us with the
4b2-HEK293 cell line Shahrokh Padrah is thanked for his technical
a3b4 and a4b4 nAChR
a
a
Accordingly, binding affinity to and selectivity for the nAChRs
are not greatly affected when the carbamate nitrogen has one,
fairly small, hydrophobic substituent. However, increasing the
size of the substituent leads to decreased binding affinity for
assistance. This work was supported by the Lundbeck Foundation,
the Carlsberg Foundation and the Danish Medical Research
Council.
the
analog 13e.
a4b2 and the a3b4 nAChR, as exhibited by the phenylpropyl
Supplementary data
Finally, compounds 5–13e displayed agonistic properties at the
3b4 nAChR in the FMP assay (Table 2), which confirmed the obser-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.11.011.
a
vations of earlier studies in which DMABC derived compounds
were found to be agonists at the 4b2 and the
3b4 nAChRs.16–18
As can be seen from Tables 1 and 2, the rank order of agonist
potencies displayed by compounds 5–13e at the 3b4 nAChR was
a
a
References and notes
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