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Organic & Biomolecular Chemistry
Page 2 of 11
DOI: 10.1039/C6OB01974A
COMMUNICATION
Journal Name
Figure 1 – Possible treatments to assist smoking cessation
Presence of
bridge
Presence of
methylamine
Substitution at
bridge
Increased substitution
at amine
Another compound that has stimulated interest in the area and is of
direct relevance to the work described herein is the general nAChR
antagonist mecamylamine (3). Mecamylamine (MA) was initially
developed as a treatment for hypertension and was sold as
Inversine® by Merck for many years until the development of β-
blockers which were more effective and have an improved side-
effect profile.9 More recently, interest in mecamylamine has been
reinvigorated by observations that it has anti-addictive properties
against not only nicotine but other drugs of abuse.10 For example,
clinical trials have shown that smokers are more likely to quit and
more likely to be abstinent after 12 months when assisted by MA in
combination with NRT - a remarkable 40% remained abstinent after
12 months.11 MA has been shown to reduce cue-induced craving in
human cocaine addicts.12 In human clinical studies MA was shown
to diminish the euphoric and stimulant effects of ethanol and was
also found to reduce the self-reported desire to consume ethanol in
healthy male and female non-smoking social drinkers.13 The
significance of this is enhanced by the fact that, in addition to the
well known health consequences of excessive alcohol consumption,
there is growing evidence of a direct link between alcohol intake and
some cancers.14 MA has been shown to reduce self-administration
(a model for addiction) of a variety of drugs of abuse such as
ethanol, opiates and stimulants in animal models.15 There are also
indications that varenicline may have some role to play in the
treatment of cocaine addiction.16
7
7
H
H
1
1
N
N
2
2
6
6
3
3
4
4
5
5
Absence of
methyl groups
Presence of
methyl groups
Features necessary for activity
Alterations which decrease activity
Figure 2 – Factors associated with the activity of mecamylamine
Analysis of the current SAR data highlights two significant points;
increased steric bulk (for H to Me) at positions 2 and 3 (Figure 2)
improves activity, and although the bridge is important, the
relationship of the amine with the 1-carbon and 2-carbon variant
has not been examined. The current study started with the concept
of increasing the steric bulk around the amine and also the
examination of the importance of amine relative stereochemistry.
Previous syntheses of MA, although concise, have relied on
camphene derivatives, which meant exploring options other than
methyl groups adjacent to the amine would be synthetically
challenging.26,27 In order to explore these options an alternative
new synthetic route would be required.
As a model study, the preparation of MA from norboranone (4) was
attempted – if this methodology were successful it should allow
alternative groups to be installed in the place of methyl units
around the amine. Treatment of norboranone (4) with LDA at low
temperature gave the expected enolate which was methylated with
methyl iodide forming 5 in 84% yield. Note that the addition of the
electrophile occurred from the exo-face due to the ‘picket fence’
effect.28 Attempts to add a second methyl group by treatment with
LDA and methyl iodide led to incomplete reaction. However, the
use of NaHMDS, in place of LDA, followed by treatment with methyl
iodide generated the dimethylated ketone 6, and exposure of this
ketone to methyl lithium formed tertiary alcohol 7. Again the
‘picket-fence’ effect directed the methyl lithium to the exo-face
with no evidence of alternative stereoisomers by NMR
It is currently unknown whether the general activity of MA at
different nAChR subtypes is important for activity, or indeed
whether fine-tuning the structure could produce a more effective
compound by enhancing its activity at a specific receptor subtype;
α3β415(f) and α4β217 are currently considered prime candidates.
Moreover, the generation of subtype-specific compounds can help
elucidate the role of different subtypes within the CNS and offer
insight into other disorders.18 Surprisingly, despite the long history
of MA the influence of stereochemistry on activity was only assessed
in 2001.19 Furthermore, MA seems to have effects in other disorders
such as Tourette’s Syndrome20 and nAChR’s have been postulated to
have roles in many other neuropsychiatric disorders.18
In addition, MA is an attractive lead for drug development since the
pharmacokinetics are well understood, bioavailability of MA is high
and the compound is known to readily cross the blood-brain
barrier.10 MA has been used by millions of patients which indicates
that serious side-effects are rare and are typically anti-cholinergic in
nature e.g. dry mouth and constipation. Additionally, doses for anti-
addictive action are considerably lower than those required for anti-
hypertensive activity. The work described above indicates that the
development of analogues merits further investigation.
spectroscopy.
The seminal SAR studies of MA have been completed by Corne,21
Stone,22 Wragg,23 Herr24 and Suchocki.25 The key points, of particular
relevance to this study, are summarised in Figure 2. More recent
studies by Crookes have developed some interesting dimeric and
trimeric systems.26
Scheme 1 – Formation of the tertiary alcohol
2 | J. Name., 2012, 00, 1-3
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Mangan, David
