Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity

Article abstract of DOI:10.1021/jm051196m

We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the α4β2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was foun

Full text of DOI:10.1021/jm051196m

J. Med. Chem. 2006, 49, 2673-2676
2673
Synthesis and Pharmacological Evaluation of
Novel 9- and 10-Substituted Cytisine Derivatives.
Nicotinic Ligands of Enhanced Subtype
Selectivity
Sheela K. Chellappan,† Yingxian Xiao,‡
Werner Tueckmantel,§ Kenneth J. Kellar,‡ and
Alan P. Kozikowski*,†
Figure 1.
Figure 2.
Drug DiscoVery Program, Department of Medicinal Chemistry and
Pharmacognosy, College of Pharmacy, UniVersity of Illinois at
Chicago, 833 South Wood Street, Chicago, Illinois 60612,
Department of Pharmacology, Georgetown UniVersity,
3900 ReserVoir Road, NW, Washington, D.C. 20057, and
Acenta DiscoVery Inc, 9030 S. Rita Road, Suite 300,
Tucson, Arizona 85747
structural differences, but is of great societal value in terms of
possible disease treatment.
ReceiVed NoVember 28, 2005
The R4â2 nAChR is the most abundant subtype in the brain.7
Several findings suggest that R4â2 receptors are involved in
behavioral activity such as nicotine dependence, avoidance
learning, and antinociception.8 Nicotine (1) and epibatidine (2)
are both naturally occurring nAChR agonists that have attracted
interest as lead candidates for analogue synthesis aimed at
identifying structures with improved pharmacological proper-
ties.1,9,10 For example, we recently reported that introduction
of a hydrophobic or hydrogen-bonding alkynyl group into the
C-5 position of the pyridine ring of epibatidine and A-84543
(3) significantly increased the selectivity for nAChRs containing
â2 subunits.11 As part of our continuing interest in this project,
we focused on chemically modifying (-)-cytisine 4, a natural
chiral quinolizidine alkaloid with a unique tricyclic structure
(Figure 1).12
Abstract: We report the synthesis and pharmacological properties of
several cytisine derivatives. Among them, two 10-substituted derivatives
showed much higher selectivities for the R4â2 nAChR subtype in
binding assays than cytisine. The 9-vinyl derivative was found to have
a very similar agonist activity profile to that of cytisine.
Neuronal nicotinic acetylcholine receptors (nAChRs) belong
to a heterogeneous family of pentameric ligand-gated ion
channels which are differently expressed in many regions of
the central nervous system (CNS) and peripheral nervous
system.1,2 In the CNS, nAChRs regulate transmitter release, cell
excitability, and neuronal integration. Neuronal nicotinic recep-
tors constitute therapeutically relevant targets for the treatment
of neurodegenerative disorders and other CNS disorders includ-
ing Alzheimer’s and Parkinson’s disease, Tourette’s syndrome,
schizophrenia, attention deficit disorder, anxiety, and pain.
Moreover, as the addictive properties of tobacco products are
due to the nicotine contained therein, nAChRs also become
important targets for the discovery of medications for use in
smoking cessation.3
The nAChRs are composed of various combinations of
different subunits, of which 17 (R1-R10, â1-â4, γ, δ, and ꢀ)
are known at present. Different subunit combinations define the
various nAChR subtypes, and different receptor subtypes have
characteristic pharmacological and biophysical properties, as
well as different locations within the nervous system.4 Therefore,
subtype selectivity is an important issue for the effectiveness
and safety of nicotinic therapeutics.
(-)-Cytisine (4) is reported to behave as a partial agonist at
the R4â2 nAChR with EC50 ≈ 1 µM and possess a low
nanomolar binding affinity (Ki ≈ 1 nM).13-16 [3H]Cytisine is
frequently used as a radioligand in the study of nAChRs.13,17
Three total syntheses of cytisine18 were achieved in the 1950s.
Recently, further interest in this alkaloid was stimulated by the
two alternative approaches to cytisine reported by Coe19 and
O’Neill et al.20 Their efforts eventually resulted in the discovery
of varenicline (5), a substantially re-engineered version of
cytisine which has become a clinical candidate for use in
smoking cessation.21 Following these reports, several other
reports, including two enantioselective routes to this alkaloid
as well the synthesis of other novel cytisine analogues have
been published.22-24
While a host of nAChR ligands have been identified, there
is still a substantial need to discover subtype-selective ligands
that can be used to establish the physiological and pathophysi-
ological significance of each of the receptor subtypes. As is
now apparent from clinical results obtained with a variety of
drugs, both the safety and efficacy of therapeutic agents often
depend on their subtype selectivity. While, as noted, a large
number of nicotinic agonists and noncompetitive antagonists
exist, very few of these are subtype-selective.1,6 Exquisite
subtype selectivity is difficult to achieve because of the large
number of possible subtypes together with their relatively subtle
Our own work in the nicotine area has been ongoing for
approximately four years. Herein we report the synthesis and
pharmacological evaluation of novel 9- and 10-substituted
cytisine derivatives. To the best of our knowledge, the present
work provides the first example of cytisine derivatives with 10-
substitution. We modified O’Neill’s synthetic strategy so as to
allow implementation of the desired structural changes.20
At the onset of our work in this area, we chose to synthesize
some simplified cytisine analogues. Deletion of the C-1/C-13
bond in cytisine yields structure 6 (Figure 2). This compound
and its isomers 7a and 7b can be prepared from piperidin-3-yl-
and -4-ylmethanol by N-protection, iodide installation, and then
reaction with R-pyridone, followed by deprotection (for the
synthetic scheme, see Supporting Information).
* To whom correspondence should be addressed. Phone: 312-996-7577.
Fax: 312-996-7107. E-mail: kozikowa@uic.edu.
† University of Illinois at Chicago.
‡ Georgetown University.
As initial biological assays revealed that the binding affinities
of compounds 6a-c and 7a,b at the nAChR subtypes were
§ Acenta Discovery Inc.
10.1021/jm051196m CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/06/2006

2674 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9
Letters
Scheme 1a
Scheme 3a
a Reagents and conditions: (a) BH3-THF, THF, 0 °C, 5 h, 85%; (b)
CH2(OMe)2, BF3‚OEt2, CH2Cl2, 0 °C, 3 h, 85%.
Scheme 2a
a Reagents and conditions: (a) PdCl2(PPh3)2, Dioxane, 120 °C, 1 h, 73%;
(b) TFA, CH2Cl2, 30 min, 81%. (c) Pd (PPh3)4, K2CO3, DME/H2O, 85 °C,
15 h, 87%; (d) TFA, CH2Cl2, 30 min, 85%.
Figure 3.
ceeded smoothly to afford the 10-hydroxymethyl derivative 17
in 97% yield.
We further expanded the SAR of cytisine by preparing some
additional analogues starting from (-)-cytisine itself. Most of
the previously reported SAR of this molecule has focused on
modifications at the alicyclic nitrogen (position 3) and also on
the 9- and 11- positions of the pyridone ring.24,29,30 Moreover,
a recent report showed that substitution at the 6-position could
be brought about via a novel N-acyl migration reaction.31 As
the biological activity of some of these known compounds
has not been described in full, we selected four of the re-
ported compounds together with new analogues in order to more
fully flesh out our SAR studies. Following a literature pro-
cedure we synthesized the N-Boc-protected 9-bromocytisine 18
and its Stille coupling product with tri-n-butylvinylstannane.29
Final deprotection with TFA afforded the derivative (-)-19
(Scheme 3).29b
a Reagents and conditions: (a) Pd(PPh3)4, DMF, 130 °C, 15 h, 79%; (b)
LiAlH4, THF, -20 °C, 3.5 h, 59%; (c) BnBr, CH3CN, reflux, 2 h; (d) H2
(1 atm), PtO2, Et3N, MeOH, rt, 15 h, cis:trans ) 5:1; cis, 67%; (e) MsCl,
Et3N, DCM, 0 °C, 30 min, 84%; (f) toluene, reflux, 3 h, 83%; (g) TFA, rt,
3 h, 91%; (h) H2 (1 atm), 10% Pd-C (1 equiv w/w), MeOH, rt, 15 h; (i)
H2 (1 atm), 20% Pd(OH)2-C (0.1 equiv), (Boc)2O, MeOH, reflux, 30 min,
92%; (j) TFA, CH2Cl2, rt, 1 h, 87-93%.
much lower (Supporting Information, Table A) than that of
cytisine,16 we subsequently retained the core tricyclic structure
while placing substituents on the pyridone ring. Our first ob-
jective was to introduce a hydroxymethyl group at the 10-posi-
tion. The modified starting material required for this purpose,
compound 10, was prepared by borane reduction of com-
mercially available 2-chloro-6-methoxyisonicotinic acid (8),25
followed by hydroxyl protection (Scheme 1).
We succeeded in carrying out a Suzuki coupling reaction of
18 with various boronic acids 20 to afford 21a-c (Scheme 3).
The synthesis of 21a using the Stille coupling procedure29 has
already been reported. The 6-substituted derivatives 22 and 23
were also prepared following known procedures (Figure 3).31
Pd-catalyzed Stille coupling of the preformed stannane20 11
with 10 under the optimized conditions proceeded smoothly to
afford compound 12 in 79% isolated yield (Scheme 2). With
trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) as the
catalyst, the reaction proceeded much faster, but gave low yields
especially on scale-up. The in situ Stille coupling reaction gave
inferior results.20 Our attempts to repeat O’Neill’s ester reduction
at room temperature gave only the over-reduced methyl deriva-
tive. The required alcohol was obtained when the reduction was
carried out using 1 M LiAlH4 solution in THF at -20 °C for
3.5 h. Following the strategy of O’Neill with some modifica-
tions, and after deprotection of the methoxymethyl (MOM)
group with trifluoroacetic acid (TFA) at room temperature, we
obtained N-benzyl-10-(hydroxymethyl) cytisine (14).
In vitro binding affinities (Ki values) of the eight cytisine
analogues 15, 17a, 19, 21a, 21b, 21c, 22, and 23 were measured
at six defined nAChR subtypes expressed in stably transfected
cell lines, using competition binding assays as previously
reported (Table 1).10,16,32 In comparison to cytisine, the 10-
methyl derivative 15 showed a similar binding affinity to R4â2
nAChRs, the major subtype in brain, but its affinities to the
other subtypes were lower than those of cytisine. Thus, the
selectivity of 15 for the R4â2 subtype over the other subtypes
was improved significantly. This is especially true for selectivity
between the R4â2 subtype and R3â4 subtype, the main subtype
of ganglionic nAChRs. The affinity ratio of R3â4/R4â2 is larger
than 3000-fold, which puts compound 15 among the most
selective cytisine analogues that have been reported to date. The
racemic nature of 15 probably will not have a substantial impact
on this selectivity ratio. Interestingly, compound 17a with a 10-
hydroxymethyl group showed reduced activity at all subtypes,
but again displays a larger R3â4/R4â2 affinity ratio. The 9-vinyl
compound 19 was slightly more potent than cytisine at some
of the nAChRs, but overall it behaves much like cytisine. All
of the other six cytisine analogues showed considerably reduced
binding affinities at all nAChRs. Compound 21a did, however,
retain its selectivity for the R4â2 nAChR.
Attempted N-debenzylation of this compound using a variety
of methods failed. Several catalytic hydrogenation protocols
as well as the use of allyloxycarbonyl chloride26 resulted in
either no reaction or the formation of complex mixtures.
Prolonged hydrogenation over 10% Pd-C at room temperature
and 1 atm in MeOH gave the over-reduced product 15. Our
difficulty in carrying out this step was finally resolved by
hydrogenation over Pd-C in the presence of (Boc)2O.27
A
mixture of two products was formed, separation of which by
semipreparative HPLC gave the less polar over-reduced com-
pound 16 and the more polar 10-hydroxymethyl derivative 17.
Final N-Boc deprotection with TFA28 gave the 10-substituted
racemic cytisine derivatives 15 and 17a. Later we found that,
under optimized conditions (20% Pd(OH)2-C, (0.1 eq), H2 (1
atm), (Boc)2O, MeOH, 5 min, reflux), N-debenzylation pro-
The above eight cytisine analogues were next tested for their
agonist activities at the two major neuronal nAChR subtypes,

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9 2675
Table 1. Binding Affinities and Calculated Lipophilicities of (()-Epibatidine (2), (-)-Cytisine (4), and Cytisine Analogues at nAChR Subtypesa
Ki (nM)b
affinity ratio
(R3â4/R4â2)
calculated
ligand
R2â2
R2â4
R3â2
R3â4
R4â2
R4â4
forebrain
ClogPc
rac-15
rac-17a
7.5
32
0.7
820
8000
500
180
300
9.0
8100
28000
1700
75000
50000
540
467
28
6700
10000
95
66000
140000
23000
320000
280000
1.9
11
0.73
420
8200
390
38
68
2.3
20
38
5.2
3526
909
130
157
17
59
13
18
10
1.15
-0.32
1.50
2.56
4.38
2.73
0.57
0.71
1.81
0.60
(-)-19
(-)-21a
12000
36000
6000
250000
300000
3300
13000
590
33000
20000
3100
21000
1200
48000
23000
0.06
(-)-21b
(-)-21c
(-)-22
17000
14000
24000
16000
(-)-23
(()-epibatidine (2)
(-)-cytisine (4)
0.02
1.07
0.09
5.41
0.04
37.20
0.57
217.00
0.06
1.51
0.16
2.10
1.92
144
a Competition binding assays were carried out in membrane homogenates of stably transfected cells or rat forebrain tissue as described previously.16 The
nAChRs were labeled with [3H]epibatidine. The Kd values for [3H]epibatidine used for calculating Ki values were 0.02 for R2â2, 0.08 for R2â4, 0.03 for
R3â2, 0.3 for R3â4, 0.04 for R4â2, 0.09 for R4â4, and 0.05 for rat forebrain. b Ki values of the cytisine analogues shown are the mean of three to five
independent measurements. For clarity and to save space, the SEM for the Ki values shown are omitted, but in all cases were less than 45% of the mean
values. The Ki values of epibatidine (2) and cytisine (4) were published previously and are shown here for comparison.16 c The ClogP values are calculated
using the online version of Syracuse Research Corporation’s LogKow/KOWWIN program; J. Phram. Sci. 1995, 84, 83-92.
penetration of the blood-brain barrier (BBB).36 Lipophilicity
Table 2. Comparison of Agonist Activities of (-)-Nicotine and (-)-19
at Two Major nAChR Subtypes, R3â4 and R4â2
is one of the important indicators for predicting absorption and
BBB penetration.37 Compound 19 has a higher calculated ClogP
value than that of cytisine (Table 1). Its ClogP value is between
those of nicotine (1.00) and epibatidine (1.80), both of which
penetrate the BBB easily. Though far from conclusive, these
data indicate that compound 19 may have an improved BBB
penetration in comparison to cytisine. In light of the similarity
of 19 and cytisine in relation to their binding affinity profiles
and agonist activity profiles, if 19 is confirmed to have a better
absorption and BBB penetration profile, it may be a better
candidate to use in targeting CNS receptors in vivo, in particular
for use in smoking cessation.
R3â4 nAChRsb
R4â2 nAChRsc
relative Emax
EC50
relative Emax
EC50
compound (µM) (% of nicotine Emax
(-)-nicotine 35 ( 8 100
(-)-19 30 ( 7 83 ( 3
)
(µM)
(% of nicotine Emax)
10 ( 1
1.3 ( 0.4
100
22 ( 2
a Agonist activities were measured using 86Rb+ efflux assays. Values
shown are the mean ( standard error of three independent experiments
performed in quadruplicate. b KXR3â4R2 cells stably expressing rat R3â4
nAChRs were used as described previously.16,32,33 c A procedure for
measuring 86Rb+ efflux from SH-EP1-hR4â2 cells was adopted15 with minor
modifications.
R3â4 and R4â2, using 86Rb+ efflux assays previously re-
ported.15,32 They were tested at four concentrations, 0.1, 1, 10,
and 100 µM. Compound 19 stimulated 86Rb+ efflux from cells
expressing either R3â4 or R4â2 nAChR subtypes. The other
seven compounds failed to show agonist activity at any of the
concentrations used at these two nAChR subtypes. Compound
19 was further evaluated for its agonist potency and efficacy
(Table 2). Consistent with its higher binding affinity at R4â2
than at R3â4 nAChRs, the compound was 20-fold more potent
at the R4â2 subtype (EC50 ) 1.3 µM) than at the R3â4 subtype
(EC50 ) 30 µM). Compared to the efficacy of (-)-nicotine,
the maximal efficacies of 19 were 83% and 22% of those of
nicotine at the R3â4 receptors and R4â2 receptors, respectively.
The overall agonist activity profile of 19 is very similar to that
of cytisine.15,33 Compounds 15 and 17a did not show agonist
activity at R4â2 nAChRs despite their high selectivity for this
nAChR subtype in the binding assays. We tested these two
compounds at concentrations from 0.1 µM to 100 µM for their
antagonist activities at the R4â2 and R3â4 receptors. At
concentrations up to 10 µM, the compounds did not significantly
block nicotine stimulated responses. However, at 100 µM, both
compounds inhibited more than 50% of the function of the R4â2
nAChR subtype but only slightly inhibited the function of the
R3â4 nAChR subtype. These results indicate that the two 10-
substituted cytisine analogues, compound 15 and 17a, are weak
antagonists of the R4â2 nAChR subtype. These two compounds
appear to have high affinity for the R4â2 nAChR subtype in its
desensitized conformation (i.e., in the receptor binding assays),
but low affinity for the receptors in their resting conformation,
as shown by their low potency in functional assays. This is
typical of most classical nicotinic ligands.34
In conclusion, we have synthesized several new cytisine
derivatives. The 10-substituted analogues 15 and 17a are more
than 3000-fold and 900-fold selective for the R4â2 subtype over
the R3â4 nAChR subtype in binding assays, respectively,
making them among the most discriminating nicotinic ligands
that have been derived from cytisine. The 9-vinyl derivative
19 showed very similar functional features to those of cytisine.
The fact that compound 19 may have an improved ability to
penetrate the BBB adds to the value of this compound as a
research tool. Therefore, compared to cytisine, ligand 19 may
be a better compound for targeting CNS nicotinic receptors.
Further efforts to characterize the pharmacological properties
of these three compounds both in vitro as well as in vivo (drug
discrimination) are underway.
Acknowledgment. This work was supported by the National
Institutes of Health (Grant R01 DA017980). Authors thank Dr.
Ronald J. Lukas (Barrow Neurological Institute, Phoenix,
Arizona) for the generous gift of the stable cell line, SH-EP1-
hR4â2, and Dr. Zhi-Liang Wei for the synthesis of compound
6a.
Supporting Information Available: Detailed experimental
procedures with spectroscopic data for all new compounds are
available at http://pubs.acs.org.
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