Structure-activity studies with ring E analogues of methyllycaconitine. Synthesis and evaluation of enantiopure isomers of selective antagonist at the α3 nicotinic receptor

Article abstract of DOI:10.1016/S0223-5234(02)01353-3

The four diastereomers 4a-d of methyllycaconitine (MLA) analogue 3 (R = (CH₂)₃Ph, R′ = CH₃) have been synthesized in enantiomerically pure form by coupling both (S)- and (R)-2-(methylsuccinimido)benzoic acid (5a and 5b) with both (S)- and (R)-3-hydroxymethyl-N-(3-phenyl) propylpiperidine (6a and 6b) using TBTU. These compounds were assayed for potency as nicotinic acetylcholine receptor (nAChRs) antagonist. All the four diastereomers showed the same potency at both the α3 and α7 receptors as racemic compound 3. This indicates that the binding at nicotine acetylcholine receptors (nAchRs) is probably non-stereospecific.

Full text of DOI:10.1016/S0223-5234(02)01353-3

Eur. J. Med. Chem. 37 (2002) 469–474
www.elsevier.com/locate/ejmech
Original article
Structure–activity studies with ring E analogues of
methyllycaconitine. Synthesis and evaluation of enantiopure
isomers of selective antagonist at the a3 nicotinic receptor
K.A. Ismail a,*, S.C. Bergmeier b
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Uni6ersity of Alexandria, Alexandria, Egypt
b Department of Chemistry and Biochemistry, Ohio Uni6ersity, Athens, OH 45701, USA
Received 23 October 2001; received in revised form 19 February 2002; accepted 20 February 2002
Abstract
The four diastereomers 4a–d of methyllycaconitine (MLA) analogue 3 (R=(CH2)3Ph, R%=CH3) have been synthesized in
enantiomerically pure form by coupling both (S)- and (R)-2-(methylsuccinimido)benzoic acid (5a and 5b) with both (S)- and
(R)-3-hydroxymethyl-N-(3-phenyl) propylpiperidine (6a and 6b) using TBTU. These compounds were assayed for potency as
nicotinic acetylcholine receptor (nAChRs) antagonist. All the four diastereomers showed the same potency at both the a3 and a7
receptors as racemic compound 3. This indicates that the binding at nicotine acetylcholine receptors (nAchRs) is probably
´
non-stereospecific. © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: methyllycaconitine; diastereomers; enantiomers; 2-(methyl-succinimido)benzoic acid; nicotine acetylcholine receptors
phenylpropyl chain (3, R=(CH2)3Ph, R%=CH3). A
1. Introduction
second significant finding was that unlike MLA, ana-
logues such as 3 show moderate selectivity for the
heteromeric a3-nAChR as compared to the a7-nAChR
(a3: IC50 11.4 mM, a7: IC50 111 mM). A few other
examples of simpler analogues of MLA have been
reported as well [7–15]. 13C NMR and optical rotation
have been used to characterize the absolute configura-
tion of the methylsuccinimide moiety in MLA as S
[16,17].
Our previous preparation of MLA analogue 3 pro-
duced completely racemic products. If 3 was a direct
analogue of MLA we would need the C3-(S), C3%-(S)
enantiomer [18]. It was quite possible that other bind-
ing modalities may be operative in our analogue 3
relative to MLA. Thus it would seen appropriate that
all four diastereomers be prepared and evaluated rather
than only the C3-(S), C3%-(S) enantiomer.
It is becoming increasingly evident that different
nicotinic acetylcholine receptor (nAChR) subtypes me-
diate a variety of important physiological functions.
Furthermore, nAChRs have been linked to a variety of
disease states [1,2]. The involvement of specific nAChR
subtypes in the disease states remains to be elucidated.
The development of subtype-specific nAChR ligands
should not only facilitate our under-standing of these
disease states, but may lead to novel treatment strate-
gies for these diseases as well.
Methyllycaconitine (MLA) is a norditerpenoid alka-
loid that has seen extensive use as an antagonist at the
a7-nAChR [3,4]. We had reported previously on the
synthesis and evaluation of a series of racemic simple
analogues 3 of MLA [5,6] (Fig. 1) that act as micromo-
lar inhibitors at nAChRs. Our previous reports pro-
duced two significant findings about our ring E
analogues 3. First, optimal potency is observed when
the piperidine ring nitrogen is substituted with a 3-
In this paper we report the synthesis and characteri-
zation of all four diastereomers of our MLA analogue
4 (R=(CH2)3Ph, R%=CH3) in enantiomerically pure
form. These compounds have been assayed for potency
by determining their ability to displace 125I-a-(BGT)
binding from a rat brain membrane preparation.
* Correspondence and reprints
E-mail address: kadiga99@yahoo.com (K.A. Ismail).
´
0223-5234/02/$ - see front matter © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S0223-5234(02)01353-3

470
K.A. Ismail, S.C. Bergmeier / European Journal of Medicinal Chemistry 37 (2002) 469–474
Fig. 1. Methyllycaconitine and ring E analogue.
2. Chemistry
The synthesis of enantiomerically pure alcohol 6 was
a bit more challenging. The availability of optically
pure nipecotic acid 9 via resolution provided us with an
obvious starting material. Resolution of nipecotic acid
was achieved via fractional crystallization of the cam-
phorsulfonic acid (CSA) salt [20]. Pure (S)-nipecotic
acid 10a was obtained using (S)-CSA and pure (S)-
nipecotic acid 10b was obtained using (R)-CSA. Acyla-
tion of either 10a or 10b with hydrocinnamoyl chloride
provide amides 11a or 11b in 70 and 75% yield respec-
tively. The carboxylic acid and amide of 11a and 11b
were concurrently reduced with LiAlH4 [21] to produce
(S)- and (R)-3-hydroxymethyl-N-(3-phenyl) propyl-
piperidine 6a and 6b in good yield (Fig. 4).
In order to prepare the four diastereomers in enan-
tiomerically pure form we will need both enantio-
mers of 2-(methylsuccinimido)benzoic acid
5 and
3-hydroxymethyl-N-(3-phenyl)propylpiperidine 6 (Fig.
2).
The synthesis of the acid derivative 5 involves the
condensation of methylsuccinic anhydride with an-
thranilic acid [5,9]. The needed optically pure anhy-
drides 8a and 8b were prepared by dehydration of the
corresponding commercially available acids 7a and 7b,
respectively, using acetyl chloride [19] (Fig. 3). The
synthesis of (S)- and (R)-2-(methylsuccinimido) benzoic
acid 5a and 5b has been accomplished in excellent yield
by the fusion of anthranilic acid with (S)- and (R)-
methylsuccinic anhydride [5,9] (Fig. 3).
Determination of the optical purity of 6a and 6b was
achieved by 1H NMR spectroscopic analysis of the
(R)-a-methoxy-a-trifluoromethyl phenylacetate esters.
Fig. 2. Synthesis of ring E analogue.
Fig. 3. (a) CH3COCl, reflux, 3 h, (b) anthranilic acid, neat, 145 °C, 0.1 mmHg, 3 h.

K.A. Ismail, S.C. Bergmeier / European Journal of Medicinal Chemistry 37 (2002) 469–474
471
Fig. 4. (a) (S)- or (R)-10-camphorsulphonic acid (CSA), acetone:water recrystallize. (b) Hydrocinnamoyl chloride, Et3N, DMAP. (LiAlH)4, reflux,
24 h.
Fig. 5. Coupling conditions for ring E analogue.
Based on the 1H NMR we can conclude that both
amino alcohols are \98% enantiomerically pure.
Coupling of the 2-(methylsuccinimido)benzoic acid
5a and 5b to the amino alcohols 6a and 6b using
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium te-
trafluoroborate (TBTU) produced our target com-
pounds 4a-d (Fig. 5). Our target compounds 4a–d were
converted to their water-soluble hydrochloride salts
prior to biological evaluation.
foils. Visualization was accomplished with UV light/or
phosphomolybdic acid solution followed by heating.
Purification of the reaction products was carried out by
flash column chromatography using glass column dry
packed with silica gel (230–400 mesh) according to the
method of Still [25]. Organic solutions were dried over
MgSO4; evaporated refers to removal of solvent on a
rotary evaporator under reduced pressure. Melting
points were determined using a Thomas Hoover capil-
lary melting point apparatus and are uncorrected. IR
spectra were obtained on salt plates in KBr pellet or in
CCl4, using a Nicolet Protege 460 model spectrometer.
3. Biological activity
1
Peaks are reported in cm−1. H and 13C NMR spectra
were recorded on a Bruker 250 MHz spectrometer with
TMS as internal standard in CDCl3 unless otherwise
noted. Mass spectral data were determined at the Ohio
State University Chemical Instrument center with a
Kratos MS-30 mass spectrometer. Optical rotations
were recorded on a Perkin–Elmer 241 Polarimeter
using mercury or sodium spectral lines at 435 or 589
nm, respectively. Solvents were dried and purified ac-
cording to the recommended procedures. All reactions
were carried out under an argon atmosphere, unless
otherwise noted.
The four prepared diastereomers 4a–d were assayed
for potency by determining their ability to displace
125I-a-bungarotoxin ([125I] a-BGT) [22] and [3H]
nicotine [23] binding from a rat brain membrane prepa-
ration. We have also assayed these analogues using
adrenal chromaffin cells (primarily a3 receptors) as
functional assay [24].
Our results to date indicate that all of the four
diastereomers showed the same potency at both the a3
and a7 receptors. This indicated that the binding at
nAChRs is non-stereospecific. Further pharmacological
evaluation is being carried out to determine the type of
binding (competitive versus non-competitive).
4.1. (S)-Methylsuccinic anhydride (8a)
A solution of (S)-methylsuccinic acid 7a (0.5 g, 3.8
mmol) in acetyl hloride (0.8 ml, 11.3 mmol) was
refluxed for 3 h. The mixture was evaporated to give
white crystals which were washed twice with cold Et2O
and dried under vacuum to give 0.42 g (97%) of 8a,
4. Experimental
General. Thin layer chromatography (TLC) was per-
formed on Whatman coated silica gel F254 aluminum

472
K.A. Ismail, S.C. Bergmeier / European Journal of Medicinal Chemistry 37 (2002) 469–474
m.p. 45–47 °C; IR (KBr) 1795, 1790, 1210. [h]D
−
4.7. (S)-N-Hydrocinnamoylpiperidine-3-carboxylic acid
(11a)
33.9° (c 1.0, CHCl3) and −37.2° (c 3.5, dioxane),
1
([h]D−36.5°, (c 3.5, dioxane)) [16]. H NMR (DMSO-
d6) l 3.27 (m, 1H), 3.06 (dd, 1H, J=19.5, 10 Hz), 2.69
(dd, 1H, J=19.5, 7.8 Hz), 1.23 (d, 3H, J=7.8 Hz).
To a 0 °C solution of (S)-nipecotic acid salt 10a (0.5
g, 1.4 mmol) in CH2Cl2 (10 ml), Et2N (10 ml, 6.9 mmol)
and DMAP (0.2 g, 0.14 mmol), hydrocinnamoyl chlo-
ride (0.24 ml, 1.6 mmol) was added dropwise. The
mixture was stirred overnight at r.t. The solution was
acidified with 1 N HCl, the organic layer was separated,
dried over MgSO4, filtered and concentrated. The
residue was chromatographed (50% EtOAc in hex-
anes+0.5% HOAc) to give 0.25 g (69.4%) of 11a as
white crystals; m.p. 141–143 °C; [h]D+51.58° (c, 1.0,
CHCl3). IR (KBr) 3452, 3022, 1725, 1613, 1597. 1H
NMR (CHCl3) l 9.85 (bs, 1H), 7.4–7.09 (m, 5H), 4.6
(bd, 1H, J=1.5 Hz), 4.05 (bd, 1H, J=1.5 Hz), 3.7 (t,
1H), 3.4 (t, 1H), 3.12 (m, 2H), 2.7 (m, 2H), 2.51 (m,
1H), 2.32 (m, 1H), 2.1 (m, 1H), 1.8 (m, 1H), 1.4 (m,
1H). 13C NMR (CDCl3) l 171.7, 141.4, 128.9, 126.5,
47.6, 46.5, 44.1, 42.5, 35.5, 35.2, 31.9, 27.5, 27.4, 25.2,
24.1. HRMS Calc. for C15H19NO3 was 261.316. Found:
261.135.
4.2. (R)-Methylsuccinic anhydride (8b)
This compound was prepared by the same procedure
as for the S-enantiomer, starting with (R)-methylsuc-
cinic acid 7b on a 0.5 g scale to give 0.4 g (93%) of 8b.
All analytical data were identical except for [h]D +34.4
(c 1.0, CHCl3).
4.3. (S)-2-(Methylsuccinimido)benzoic acid (5a)
(S)-Methylsuccinic anhydride 8a (0.1 g, 0.9 mmol)
was stirred at 40 °C, then anthranilic acid (0.12 g, 0.9
mmol) was added and the mixture was heated at
145 °C under reduced pressure (0.1 mmHg) for 3 h.
The residue was chromatographed (toluene: EtOAc:
HOAc (9: 0.5: 0.5) to give 0.19 g (95%) of 5a as
hygroscopic yellowish white crystals. [h]D −12.5° (c
1.0, CHCl3); IR (neat) 3501, 1769, 1620. 1H NMR
(CDCl3) l 10.5 (bs, 1H), 8.2 (d, 1H, J=7.5 Hz), 7.72 (t,
1H), 7.52 (t, 1H), 7.22 (d, 1H, J=7.5 Hz), 3.1 (m, 2H),
2.5 (d, 1H, J=15 Hz), 1.4 (d, 3H, J=7.5 Hz). 13C
NMR (CDCl3) 180.2, 176.4, 169.7, 134.7, 133.3, 132.9,
130.2, 129.8, 128.6, 123.7, 35.8, 16.9. HRMS Calc. for
C12H11NO4 was 233.244. Found: 233.068.
4.8. (R)-N-Hydrocinnamoylpiperidine-3-carboxylic acid
(11b)
This compound was prepared by using the same
procedure as for the (S)-enantiomer, starting with (R)-
nipecotic acid salt 10b (0.5 g, 1.4 mmol) to give 0.27 g
(75%) of 11b as white crystals. All analytical data were
identical except for m.p. 146–148 °C and [h]D −52°
(c, 1.0, CHCl3).
4.4. (R)-2-(Methylsuccinimido)benzoic acid (5b)
This compound was prepared by the same procedure
as for the (S)-enantiomer 5a, starting with (R)-methyl-
succinic anhydride 8b (0.1 g, 0.9 mmol) to produce 0.17
g (85%) of 5b. All analytical data were identical except
for [h]D +14.1 (c 1.0, CHCl3).
4.9. (S)-3-Hydroxymethyl-N-(3-phenyl)propylpiperidine
(6a)
A solution of the (S)-acid derivative 11a (0.2 g, 0.76
mmol) in THF (2 ml) was added via cannula to a
refluxing suspension of LiAlH4 (90 mg, 2.3 mmol) in
THF (1 ml). The mixture was refluxed for 24 h. After
the reaction was complete, it was cooled, diluted with
Et2O (3 mL), and water (90 ml) was added dropwise,
then stirred 5 min, 15% aqueous NaOH (90 ml) was
then added and stirred for another 5 min, then water
(0.2 ml) was again added. This gave a white precipitate,
which was filtered. The filtrate was concentrated and
dried under vacuum to give 0.16 g (94%) of 6a as a
yellow oil. [h]435 −9.4° (c 1.0, CHCl3). 1H NMR
(CDCl3) l 7.38–7.2 (m, 5H), 5.13 (s, 1H) 3.55 (m, 2H),
2.72 (bd, 1H, J=10.5 Hz), 2.6 (t, 3H), 2.31 (t, 2H),
2.11 (t, 1H), 2.01 (t, 1H), 1.9–1.48 (m, 6H), 1.27–1.04
(m, 1H). 13C NMR (CDCl3) l 142, 127, 125, 66.5, 57,
56, 38, 35, 28, 27, 24. HRMS Calc. for C15H23NO was
233.326. Found: 233.176.
4.5. (S)-Nipecotic acid salt (10a) [20]
(S)-10-camphorsulfonic acid (9 g, 38.7 mmol) was
added to a stirred hot solution of racemic nipecotic acid
9 (5 g, 38.7 mmol) in acetone (70 ml), water was added
to dissolve. The solution was cooled to r.t. and allowed
to stand overnight. The precipitate was filtered and
recrystallized three times with acetone/water (6/1, v/v)
to afford 2 g of 10a as white needles (14%); m.p.
222–224 °C; [h]D +25.78° (c 1.0, MeOH).
4.6. (R)-Nipecotic acid salt (10b)
The same procedure was used as for the S-enan-
tiomer starting with (R)-10-camphorsulfonic acid (9 g,
38.7 mmol) to afford 2.2 g of 10b (16%); m.p. 222–
224 °C; [h]D −26.36° (c 1.0, MeOH).

K.A. Ismail, S.C. Bergmeier / European Journal of Medicinal Chemistry 37 (2002) 469–474
473
4.10. (R)-3-Hydroxymethyl-N-(3-phenyl)propyl-
4.15. 3-(S)-3%-(R)-ester (4d)
piperidine (6b)
0.14 g (73.6%). [h]435 +20.6° (c 1.0, CHCl3). All
other data were identical to the 3-(R)-3%-(S) ester 4c.
HRMS Calc. for C27H32N2O4 was 448.553. Found:
448.237.
This compound was prepared by the same procedure
as for the (S)-enantiomer 6a, starting with the (R)-acid
derivative 11b (0.2 g, 0.76 mmol) to give 0.17 g (94%) of
the desired pure (R)-amino alcohol 6b as a yellow oil.
All analytical data were identical except for [h]435
+
9.2° (c 1.0, CHCl3).
Acknowledgements
4.11. General procedure for the condensation of the
succinimido deri6ati6e (5a or 5b) with the amino
alcohol (6a or 6b)
The authors thank Professor D.B. McKay, Division
of Pharmacology, College of Pharmacy, the Ohio State
University, Columbus, OH, for the biological evalua-
tion. We would like to acknowledge the National Insti-
tute on Drug Abuse at the National Institutes of Health
for support of this research (DA12706 and DA13939,
S.C.B.). K.A.I. would like to thank the Egyptian Cul-
tural and Education Bureau for a fellowship.
The succinimido derivative (0.34 g, 1.5 mmol) and
TBTU (0.48 g, 1.5 mmol) in CH3CN (5 ml) was stirred
at r.t. In a second flask, the amino alcohol derivative
(0.6 g, 1.5 mmol) in CH3CN (5 ml) was cooled to 0 °C
and diisopropylethylamine (0.52 ml, 3 mmol) was
added. This solution was added via cannula to the
succinimido solution. The mixture was stirred at r.t. for
24 h. The solution was evaporated to produce a brow-
nish residue which was chromatographed (EtOAc,
toluene, Et3N; 7: 2.8: 0.2) to give the products.
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0.14 g (73.6%). [h]435 +22.87° (c 1.0, CHCl3). IR
(neat) 2951, 1782, 1598. 1H NMR (CHCl3) l 8.1 (d, 1H,
J=7.5 Hz), 7.6 (t, 1H), 7.45 (t, 1H), 7.3–7.05 (m, 6H),
4.1 (d, 2H, J=6.25 Hz), 3.1 (bd, 2H, J=15 Hz), 2.9
(bd, 2H, J=15 Hz), 2.6 (m, 2H), 2.32 (m, 2H), 2.15–
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4.13. 3-(S)-3%-(S)-ester (4b)
0.15 g (78.9%). [h]435−25.6° (c 1.0, CHCl3). All other
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diastereomer 4a.
4.14. 3-(R)-3%-(S)-ester (4c)
0.15 g (78.9%). [h]435 −19.7° (c 1.0, CHCl3). 1H
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2H), 2.34 (m, 2H), 2.2–1.6 (m, 7H), 1.55 –1.45 (m,
3H), 1.4 (d, 3H, J=7.5Hz). All other data were identi-
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