Varenicline: An r4?2 Nicotinic Receptor
Partial Agonist for Smoking Cessation
Jotham W. Coe,* Paige R. Brooks,
Michael G. Vetelino, Michael C. Wirtz,
Eric P. Arnold, Jianhua Huang, Steven B. Sands,
Thomas I. Davis, Lorraine A. Lebel, Carol B. Fox,
Alka Shrikhande, James H. Heym, Eric Schaeffer,
Hans Rollema, Yi Lu, Robert S. Mansbach,
Leslie K. Chambers, Charles C. Rovetti,
David W. Schulz, F. David Tingley, III, and
Brian T. O’Neill
Pfizer Global Research and Development,
Groton Laboratories, Eastern Point Road,
Groton, Connecticut 06340
Received January 25, 2005
Abstract: Herein we describe a novel series of compounds
from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-
6H-pyrazino[2,3-h]benzazepine) has been identified for
smoking cessation. Neuronal nicotinic acetylcholine receptors
(nAChRs) mediate the dependence-producing effects of nico-
tine. We have pursued R4?2 nicotinic receptor partial agonists
to inhibit dopaminergic activation produced by smoking while
simultaneously providing relief from the craving and with-
drawal syndrome that accompanies cessation attempts. Vareni-
cline displays high R4?2 nAChR affinity and the desired in
vivo dopaminergic profile.
Within 20 years of its introduction to Britain in 1584,
King James I scorned “tobacco taking” as a “vile and
stinking custome” that is “hurtfull to the health of the
whole body”.1In the ensuing 400 years, we have learned
that although other tobacco ingredients cause the nega-
tive health effects of smoking, it is the nicotine in
tobacco that produces dependence and maintains smok-
ing behavior. Ultimately, the toll on human health today
is staggering, as half of the world’s 1.25 billion smokers
will die from smoking-related illnesses, such as chronic
obstructive pulmonary disorder, cancer, and cardiovas-
Neuronal nicotinic acetylcholine receptors (nAChRs),
which mediate fast synaptic transmission via the en-
dogenous ligand acetylcholine (ACh), have become key
targets for therapeutic approaches to treat pain, cogni-
tion, schizophrenia, and nicotine dependence.4Found
in the peripheral and central nervous systems, these
pentameric ligand-gated ion channels consist of 17
known receptor subunits (R(1-10), ?(1-4), γ, δ, and ?).5
Although a large number of neuronal subtypes have
been identified, R4?2, R3?4, and R7 predominate in the
central nervous system.
The dependence-producing effects of nicotine are
believed to be mediated in part through its action as
an agonist at R4?2 nAChRs.6,7Activation of R4?2
receptors by nicotine increases the release of dopamine
in the nucleus accumbens and prefrontal cortex,8an
effect shared by most substances of abuse, although
each through distinct neurochemical pathways.9
We sought to develop a nicotinic receptor partial
agonist of the R4?2 nAChR for smoking cessation. It was
hypothesized that an effective agent would, through its
intrinsic partial activation of the R4?2 nAChR, elicit a
moderate and sustained increase in mesolimbic dopam-
ine levels, counteracting the low dopamine levels en-
countered in the absence of nicotine during smoking
cessation attempts. Low levels of dopamine have been
associated with craving for and withdrawal from nico-
tine and are the key syndromes that precipitate relapse
to smoking behavior.10Additionally, by competitively
binding to the R4?2 nAChR, a partial agonist will shield
the smoker from nicotine-induced dopaminergic activa-
tion in the event that they smoke.11In theory, without
the nicotine-induced elevation in mesolimbic dopamine
levels, tobacco will not produce a pharmacologic reward.
Thus, we anticipated that a partial agonist would be
uniquely suited as a treatment for this condition.12
At the outset of our program only two natural
compounds were known to have partial agonist activity
at the R4?2 nAChR.13Of these,14we chose (-)-cytisine,
a natural product found in numerous plant species, as
a starting point for our studies.15(-)-Cytisine displays
potent R4?2 nAChR affinity and possesses a unique
bicyclic structure lacking rotatable bonds. A key 1994
publication showed that (-)-cytisine was a partial
agonist of the R4?2 nAChR and antagonized the recep-
tor response to its endogenous neurotransmitter, acetyl-
choline.16This work confirmed earlier reports on
(-)-cytisine’s pharmacological profile at ?2-containing
receptors: it elicited a markedly reduced response to
that of acetylcholine.17In the 1960s an early smoking
cessation study with (-)-cytisine failed to exhibit robust
efficacy,18possibly as a result of poor absorption19and
limited brain penetration.20More recently, efforts to
combine nicotine replacement therapy with the nicotinic
antagonist mecamylamine were more successful.21These
latter results of combining an agonist and antagonists
essentially creating a partial agonistssuggested that an
agent with an optimal partial agonist profile and
physicochemical properties could provide improved relief
to patients during smoking cessation attempts.
On the basis of these considerations and the struc-
tural starting point provided by (-)-cytisine, we initi-
ated synthetic efforts to generate novel compounds with
improved potency and efficacy. Our studies revealed
that R4?2 nAChR binding affinity was considerably
reduced with alterations at positions N-9 and C-5, but
maintained or improved with substitution at C-3 of
(-)-cytisine (Chart 1).22These results led us to explore
pyridone replacements based on 2. Compounds from this
series exhibited reduced affinity and weak partial
agonist activity, a result that prompted a search for
alternative templates with improved partial agonist
* Corresponding author. Phone: +1-860-441-3271. Fax: +1-860-
686-0015. E-mail: firstname.lastname@example.org.
J. Med. Chem. 2005, 48, 3474-3477
10.1021/jm050069n CCC: $30.25© 2005 American Chemical Society
Published on Web 04/23/2005
profiles. We also recognized the striking resemblance
between substructures of (-)-cytisine and morphine:
their [3.3.1]-bicyclic skeletons differ only by nitrogen
atom placement (cf. 2 vs 3, Chart 1). In the 1970s, the
[3.3.1]-bicyclic benzomorphan 3 was found to have
morphine-like antinociceptive activity, as did the modi-
fied [3.2.1]-bicyclic derivative 4; however, the N-posi-
tional [3.2.1]-bicyclic isomer, benzazapine 5, was devoid
of antinociceptive activity.23Interestingly, benzazapine
5 displayed in vivo pharmacology reminiscent of natural
nicotinic agents. On the basis of the similarity between
3 and 4, both antinociceptive compounds, we speculated
that 2 and 5 might share a similar nicotinic pharmacol-
ogy. This hypothesis was borne out, as 524was found to
be a nicotinic antagonist with a Kiof 20 nM.
Nicotinic agents share two common structural com-
ponents: an ammonium headgroup at physiological pH,
and a π-system.25Potent natural nicotinic agonists,
including epibatidine,26(-)-nicotine, (+)-anatoxin a,27
and (-)-cytisine (Ki∼ 0.07, 0.95, 4.4, 0.17 nM, respec-
tively), possess electron-deficient π-systems. As shown
in Scheme 1, we introduced an electron-withdrawing
group to benzazapine 5 by conversion to trifluoroacet-
amide 6, nitration,28and deprotection to afford (()-8,
which displayed potent R4?2 nAChR binding affinity (Ki
0.75 nM) and partial agonist activity (vide infra).
Examination of the crude nitrated reaction mixture
(6f7) revealed dinitrated products, separable on crys-
tallization. We attribute their formation to the excep-
tionally powerful and soluble nitrating agent, nitronium
triflate (CF3SO2O-NO2+). Unexpectedly, the major di-
nitrated product was 10, the result of vicinal-dinitra-
tion.29Exposure to 2.3 equiv of nitronium triflate in
CH2Cl2 gave complete consumption of 6 in 28 h to
provide 10, isolated in pure form by crystallization in
77% yield from the crude mixture, which contained
<10% of meta-isomer 9.
Isomer 10 has proven to be a very useful intermediate
for the preparation of analogues such as achiral qui-
noxaline 1, varenicline, which was prepared as follows:
Reduction of 10 to the corresponding diaminophenyl
derivative and condensation with glyoxal (sodium
bisulfite addition adduct) afforded crystalline quinoxa-
line trifluoroacetamide 11.30Deprotection, salt forma-
tion, and crystallization completed the synthesis of 1
in 44% overall yield from 5.
Varenicline (1) and (()-8 display high binding affinity
and selectivity for the rat R4?2 over the nAChR sub-
types evaluated (Table 1).31No appreciable affinity was
observed with 1 in an in vitro receptor binding panel of
nonnicotinic targets (IC50> 1000 nM).32In functional
electrophysiological assays in Xenopus oocytes express-
ing the hR4?2 nAChR, nicotine had an EC50of 15 µM.
Due to concerns about receptor desensitization, bench-
mark responses to nicotine were routinely determined
using a lower test concentration of 10 µM. At this
concentration (-)-cytisine, (()-8, and 1 were shown to
act as agonists with lower efficacy than 10 µM nicotine
(56%, 65%, and 68%, respectively).
Antagonist properties were determined by coapplica-
tion with 10 µM nicotine. Evaluating responses in the
presence of a single concentration of nicotine (10 µM)
allows the assessment of functional potencies and
agonist/antagonist properties of compounds relative to
nicotine. Potent agonists or low potency partial agonists
would not be expected to antagonize the effects of 10
µM nicotine, but agents that act as potent partial
agonists alone should functionally antagonize nicotine’s
effect at 10 µM.33The data in Table 1 reveal desirable
partial agonist profiles for (-)-cytisine, (()-8, and 1. The
full concentration-response curve of varenicline (1)
Chart 1. Related Substructures of (-)-Cytisine and
Scheme 1. Nitration Route to 7 and Varenicline, 1a
aReagents: (a) TFAA, py, CH2Cl2(94%); (b) 1.3 equiv HNO3,
2.6 equiv CF3SO2OH, -78 °C, CH2Cl2(78%); (c)  Na2CO3, aq.
MeOH (95%);  HCl, EtOAc; (d) [I] 2.3 equiv HNO3, 4.6 equiv
CF3SO2OH, 0-20 °C, 28 h, CH2Cl2(77%); (e) H2, Pd(OH)2, MeOH
(96%); (f) glyoxal, THF, H2O, 80 °C, (60)%.
Table 1. In Vitro Affinity at nAChR Subtypes and Agonist/
Antagonist Activity at the hR4?2 Receptor
% current evoked by
10 µM agent at
a[3H]-nicotine; rat cortex.b[3H]-epibatidine; IMR32 cells.c[125Ι]-
R-bungarotoxin; electroplax.d[125Ι]-R-bungarotoxin; GH4C1 cells.
(All determinations N ) 3).ePercent agonist activity of 10 µM
test compound relative to 10 µM (-)-nicotine (SEM e10%).
fPercent antagonist activity of 10 µM test compound against 10
µM nicotine (SEM e 10%).
LettersJournal of Medicinal Chemistry, 2005, Vol. 48, No. 10
revealed an EC50of 2.3 µM with a maximal efficacy of
24% relative to nicotine in this in vitro model.
We assessed the in vivo efficacy of the compounds by
their effects on mesolimbic dopamine turnover, a mea-
sure of the utilization and biosynthesis of dopamine
(Figure 1).34Concentrations of dopamine and its me-
tabolites were determined in the nucleus accumbens of
male Sprague Dawley rats (200-300 g) 1 h postdose.
The results demonstrate that nicotine has a maximal
effect on dopamine turnover (177% of controls) at 1 mg/
kg sc. The effects of 5.6 mg/kg sc (-)-cytisine, (()-8, and
varenicline (1) were 40%, 32%, and 32%, respectively,
of the maximal nicotine response. These were maximal
effects for (-)-cytisine and varenicline (1), demonstrat-
ing partial agonist behavior.
Partial agonist activity was further demonstrated
in vivo by evaluating the antagonist properties of
(-)-cytisine, (()-8, and varenicline (1). Their ability to
attenuate nicotine’s effect on the mesolimbic dopamine
system was determined in animals concurrently treated
with 1 mg/kg sc nicotine. (-)-Cytisine and (()-8 reduced
the nicotine-induced increase in dopamine turnover in
the nucleus accumbens. Unlike (-)-cytisine and (()-8,
however, at 5.6 mg/kg sc 1 fully blocked nicotine’s
effect: increases in dopamine turnover with 1 after 1 h
were the same alone and in the presence of nicotine.
These data demonstrate that all three are partial
agonists and that varenicline is more potent in vivo than
(-)-cytisine and (()-8. Figure 1 shows that (-)-cytisine,
(()-8, and varenicline (1) inhibited the nicotine response
by 36%, 54%, and 66% respectively (5.6 mg/kg sc agent
with 1 mg/kg s.c nicotine is the maximum tolerated
A related measure of partial agonist activity in vivo
included the measurement of extracellular dopamine
levels over a 6 h time course in conscious rats. Micro-
dialysis studies with nicotine and varenicline (1) mea-
suring in vivo dopamine release in rat nucleus accum-
bens confirmed the partial agonist effect of 1 (Figure
2). At a maximally effective dose of 1 mg/kg po, vareni-
cline produced a sustained increase in dopamine release
to ∼60% of the maximal nicotine effect (188% at 0.32
mg/kg sc). In addition, 1 mg/kg po varenicline reduced
the dopamine-enhancing effects of a subsequent dose
of 0.32 mg/kg sc nicotine to that of varenicline alone.
Our data show that varenicline (1) is an orally active
R4?2 nAChR partial agonist that displays ∼30-60% of
the in vivo efficacy of nicotine. Moreover, varenicline
(1) effectively blocks the nicotine response both in vivo
and in vitro, demonstrating the appropriate antagonist
profile. These attributes are desirable from the perspec-
tive of controlling nicotine dependence and reducing the
potential for side effects mediated via overactivation of
The discovery and identification of a new class of R4?2
nicotinic receptor partial agonists for the treatment of
smoking cessation has been described. Our key finding
is that benzazapine 5 is a nicotinic ligand that can be
structurally modified to afford highly selective and
potent R4?2 agents, culminating in the identification
of varenicline (1). The in vivo properties of varenicline
demonstrate its ability to attenuate the central dopam-
inergic response to nicotine while providing sufficient
and sustained dopaminergic tone to limit craving and
withdrawal. Varenicline represents a novel treatment
for tobacco dependence and has been advanced to
human clinical trials for smoking cessation.
Acknowledgment. J.W.C. would like to thank B.
L. Chenard and M. Jefson for timely encouragement.
Supporting Information Available: Experimental pro-
cedures for all new compounds and methods for in vitro and
in vivo experiments are available at: http://pubs.acs.org.
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Figure 1. Effects of (-)-nicotine, (-)-cytisine, (()-8, and 1
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All values are expressed as percentages of the effect of 1.0 mg/
kg sc nicotine (100%) ( SEM (N ) 5-10). Each compound was
administered at 5.6 mg/kg sc alone (filled bars) and with 1
mg/kg sc nicotine (shaded bars). *p <0.05 agent alone vs
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+p <0.05 and
++p <0.01: agent with nicotine vs
Figure 2. Time courses for the effects of 0.32 mg/kg sc
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Index, 10th ed.; Merck: Rahway, NJ, 1983; No. 6365.
LettersJournal of Medicinal Chemistry, 2005, Vol. 48, No. 10