Polyamine Modulation of NMDA Receptors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 993
g, 30 mmol) in dry THF (25 mL) was refluxed for 2 days. The
precipitate was filtered and washed with THF. The filtrate
was concentrated and distilled to give a colorless oil (bp 135-
140 °C/24 Torr), which was dissolved in Et2O and treated with
HCl in i-PrOH. The solution was placed in the freezer for 2
days, affording 0.98 g (32%) of N,N,N′,N′-tetraallyl-1,3-diami-
nopropane (12) dihydrochloride as colorless crystals, mp
105.8-106.5 °C. 1H NMR (CDCl3): 2.64 (pentet, 2H, J ) 7.5),
3.24-3.32 (m, 4H), 3.65-3.76 (m, 8H), 5.56-5.62 (m, 8H),
6.07-6.24 (m, 4H).
N-(3-P r op ylp ip er id in o)p ip er id in e (13).24 A mixture of
1,3-dibromopropane (27) (2.02 g, 10 mmol), piperidine (30)
(1.87 g, 22 mmol), and K2CO3 (4.14 g, 30 mmol) in dry THF
(25 mL) was refluxed for 2 days. The precipitate was filtered
and washed with THF. The filtrate was concentrated. Vacuum
distillation of the residue gave 1.51 g (72%) of N-(3-propylpi-
peridino)piperidine (13) as a colorless oil, bp 116-118 °C/0.3
Torr. 1H NMR (CDCl3): 1.41-1.76 (m, 14 H), 2.25-2.36 (m,
12 H).
4-Am in op ip er id in e (14) Dih yd r och lor id e. A mixture of
4-amino-1-benzylpiperidine (22) (2.5 g, 12.8 mmol), HCO2H (4
g), and Pd/C (10%, 1.8 g) in MeOH (80 mL) was stirred under
N2 at room temperature overnight. The catalyst was removed
by filtration and washed with MeOH. The filtrate was
concentrated and dried under vacuum, giving a light yellow
solid. This crude product (diformate) was dissolved in H2O
(20 mL), basified with solid NaOH to pH > 13, extracted with
CH2Cl2 (5 × 20 mL), and dried over Na2SO4. After removal of
the drying agent, the solution was treated with HCl in Et2O.
The precipitate was filtered and dissolved in MeOH (80 mL)
to which CH2Cl2 was added dropwise. The precipitate was
filtered and dried in vacuo to afford 1.0 g (46%) of 4-aminopi-
peridine (14) dihydrochloride as a white solid, mp >300 °C.
1H NMR (D2O): 1.80-1.98 (m, 2H), 2.27-2.36 (m, 2H), 3.08-
3.21 (m, 2H), 3.51-3.64 (m, 3H).
1-Ben zyl-4-(2-eth a n ola m in o)p ip er id in e (20) Dih yd r o-
ch lor id e. To a solution of ethanolamine (33) (4.88 g, 80 mmol)
in MeOH (40 mL) was added 1-benzyl-4-piperidone (31) (3.78
g, 20 mmol) followed by NaBH3CN (4 g). The pH of the
solution was adjusted to ∼6 with HCl in MeOH, and the
solution was stirred at room temperature under N2 for 3 days.
The reaction mixture was treated with concentrated HCl until
gas evolution ceased. The precipitate was removed by filtra-
tion, and the filtrate was concentrated. The residue was
dissolved in H2O (10 mL) and extracted with CH2Cl2. The
aqueous phase was basified with solid NaOH and extracted
with CH2Cl2. After drying over Na2SO4, the CH2Cl2 solution
was concentrated and dried under vacuum. The crude product
was dissolved in Et2O and treated with ethereal HCl. The
solid obtained was crystallized from MeOH by vapor diffusion
with Et2O to give 2.82 g (46%) of 1-benzyl-4-(2-ethanolamino)-
piperidine (20) dihydrochloride as white crystals, mp 250-
256 °C dec. 1H NMR (D2O): 1.86-2.04 (m, 2H), 2.43 (br, 2H),
3.11-3.21 (m, 2H), 3.23-3.28 (m, 2H), 3.50-3.69 (m, 3H),
3.84-3.88 (m, 2H), 4.35 (s, 2H), 7.50-7.57 (m, 5H).
are likely to provide the preferred partially protonated
species at pH 7.4.
Our working hypothesis also serves to explain other
literature results. Thus, spermine and spermidine are
highly hydrophilic compounds with ClogP values of
-2.04 and -1.65, respectively; based on the published
pK values (10.97, 10.27, 9.04, and 8.03 for spermine and
11.16, 10.06, and 8.51 for spermidine)23 there would be
between 8 and 20% of species with one unprotonated
amino group at physiological pH. Furthermore, as
flexible molecules, both would be able to adapt the
internuclear distances between the relevant amino
nitrogen atoms (i.e., a protonated amino nitrogen and
an unprotonated amino nitrogen) to meet the require-
ments of the recognition site. We envision spermine
binding to the hydrophilic (stimulatory) site more
potently than to the lipophilic (inhibitory) site. There-
fore, the hydrophilic site is occupied at 1-20 µM
spermine, resulting in enhanced [3H]MK-801 binding.
At high spermine concentrations, even the lipophilic site
becomes occupied, leading to auto-inhibition of sper-
mine-promoted [3H]MK-801 binding.
Con clu sion s
The results of our investigation of the effects of
systematic variations in the basicity, lipophilicity, and
stereochemistry of 1,3-diamines to modulate NMDA
receptors suggest the involvement of two binding sites.
Both sites appear to recognize the monoprotonated form
of 1,3-diamines. The site associated with enhancing
[3H]MK-801 binding, however, favors hydrophilic 1,3-
diamines while the site whose occupation results in
decreased [3H]MK-801 binding favors lipophilic 1,3-
diamines. The recognition site responsible for enhance-
ment of [3H]MK-801 binding appears to be stereochem-
ically sensitive, apparently preferring a specific inter-
nuclear distance between the charged (protonated)
amino nitrogen and the neutral amino nitrogen.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were measured on an
Electrothermal melting point apparatus. 1H and 13C NMR
spectra were recorded on a Bruker WM-250 spectrometer using
tetramethylsilane as internal standard for CDCl3 solutions and
the sodium salt of 2,2,3,3-tetradeutero-3-(trimethylsilyl)pro-
pionic acid as internal standard for D2O solutions. Chemical
shifts are in ppm; coupling constants, J , are reported in hertz.
Titrations were carried out on a Mettler DL40GP Memo
Titrator. Elemental analyses were performed by Atlantic
Microlab of Norcross, GA.
4-(2-Eth a n ola m in o)-2,2,6,6-tetr a m eth ylp ip er id in e (21).
To a solution of ethanolamine (33) (4.88 g, 80 mmol) in MeOH
(40 mL) was added 2,2,6,6-tetramethyl-4-piperidone (39) mono-
hydrate (3.46 g, 20 mmol) followed by NaBH3CN (4 g). The
pH of the solution was adjusted to ∼6 with HCl in MeOH, and
the solution was stirred at room temperature under N2 for 3
days. The reaction mixture was treated with concentrated HCl
until gas evolution ceased. The precipitate was removed by
filtration, and the filtrate was concentrated. The residue was
dissolved in H2O (10 mL) and extracted with CH2Cl2. The
aqueous phase was basified with solid NaOH and extracted
with CH2Cl2. After being dried over Na2SO4, the combined
extract was concentrated and dried in vacuo to give a light
yellow solid, which was crystallized from Et2O to afford 2.44
g (61%) of 4-(2-ethanolamino)-2,2,6,6-tetramethylpiperidine
(21) as white crystals, mp 98.8-99.8 °C. 1H NMR (CDCl3):
0.85 (dd, 2H, J ) 12.0), 1.13 (s, 6H), 1.20 (s, 6H), 1.87 (dd, 2H,
J ) 12.7, 3.6), 2.80 (5, 2H, J ) 5.2), 2.91 (tt, 1H, J ) 3.6, 11.7),
3.65 (t, 2H, J ) 5.2).
N,N′-Dia llyl-1,3-d ia m in op r op a n e (11) Dih yd r och lo-
r id e. To a cold (0 °C) mixture of 1,3-dibromopropane (4.04 g,
20 mmol) and H2O (1.1 mL) was added allylamine (28) (5.71
g, 100 mmol). The mixture was slowly allowed to warm to
room temperature and then heated to reflux overnight. The
resulting solution was cooled, diluted with a small portion of
H2O, and saturated with solid KOH. The mixture was then
extracted with EtOAc (3 × 40 mL), dried over Na2SO4,
concentrated, and distilled under vacuum. The distillate was
dissolved in a small amount of i-PrOH and treated with HCl
in i-PrOH. The white precipitate was filtered and dried under
vacuum to give 1.68 g (37%) of N,N′-diallyl-1,3-diaminopropane
(11) dihydrochloride as a white solid, mp 255-265 °C (dec).
1H NMR (D2O): 2.06-2.19 (m, 2H), 3.17 (5, 4H, J ) 7.9), 3.71
(d, 4H, J ) 6.7), 5.49-5.57 (m, 4H), 5.84-6.01 (m, 2H).
N,N,N′,N′-Tet r a a llyl-1,3-d ia m in op r op a n e (12) Dih y-
d r och lor id e. A mixture of 1,3-dibromopropane (27) (2.02 g,
10 mmol), diallylamine (29) (2.14 g, 22 mmol), and K2CO3 (4.14