1-Cyclohexylpiperazines as σ Receptor Ligands
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 9 2315
1
th a len -1-yl)p r op yl]p ip er a zin e (34): H NMR δ 1.18-1.40
(CH2)2], 2.20-2.80 (m, 14H, benzylic, piperazine, CHN and
CH2N), 4.90-5.40 (broad s, 1H, OH, D2O exchanged), 6.50-
7.05 (m, 3H, aromatic); GC-MS m/z 357 (M+ + 1, 18), 356
(M+, 68), 313 (27), 246 (25), 181 (100), 112 (22). Anal.
(C23H36N2O‚2HCl‚H2O) C, H, N.
1-Cycloh e xyl-4-[3-(n a p h t h a le n -1-yl)p r op yl]p ip e r a -
zin e (43): 1H NMR δ 1.08-1.98 [m, 12H, cyclohexyl (CH2)5
and CH2CH2CH2], 2.20-2.32 (m, 1H, CHN), 2.46 (t, 2H, J )
7.5 Hz, CH2N), 2.50-2.71 (m, 8H, piperazine), 3.07 (t, 2H, J
) 7.5 Hz, benzylic), 7.30-8.11 (m, 7H, aromatic); GC-MS m/z
338 (M+ + 2, 3), 337 (M+ + 1, 24), 336 (M+, 88), 293 (37), 195
(100), 181 (77), 141 (40), 111 (22). Anal. (C23H32N2‚2HCl) C,
H, N.
1-Cycloh exyl-4-[3-(5-m eth oxyn a p h th a len -1-yl)p r op yl]-
p ip er a zin e (44): 1H NMR δ 1.00-1.40 [m, 8H, cyclohexyl
(CH2)4], 1.80-2.10 (m, 4H, cyclohexyl CH2 and CH2CH2CH2),
2.20-2.41 (m, 1H, CHN), 2.45 (t, 2H, J ) 7.5 Hz, CH2N), 2.51-
2.80 (m, 8H, piperazine), 3.03 (t, 2H, J ) 7.6 Hz, benzylic),
3.97 (s, 3H, OCH3), 6.81-8.15 (m, 6H, aromatic); GC-MS m/z
368 (M+ + 2, 4), 367 (M+ + 1, 27), 366 (M+, 100), 195 (87), 181
(60), 171 (28). Anal. (C24H34N2O‚2HCl‚1/2H2O) C, H, N.
1-Cycloh exyl-4-[4-(n a p h t h a len -1-yl)b u t yl]p ip er a zin e
(45): 1H NMR δ 1.01-2.00 [m, 14H, cyclohexyl (CH2)5 and
CH2(CH2)2CH2N], 2.08-2.15 (m, 1H, CHN), 2.38 (t, 2H, J )
7.5 Hz, CH2N), 2.40-2.71 (m, 8H, piperazine), 3.08 (t, 2H, J
) 7 Hz, benzylic), 7.20-8.10 (m, 7H, aromatic); GC-MS m/z
352 (M+ + 2, 3), 351 (M+ + 1, 23), 350 (M+, 79), 307 (45), 240
(24), 181 (100), 141 (37). Anal. (C24H34N2‚2HCl‚1/3H2O) C, H,
N.
1-Cycloh e xyl-4-[5-(n a p h t h a le n -1-yl)p e n t yl]p ip e r a -
zin e (46): 1H NMR δ 1.00-2.10 [m, 16H, cyclohexyl (CH2)5
and CH2(CH2)3CH2N], 2.38 (t, 2H, J ) 7.5 Hz, CH2N) 2.50-
2.85 (m, 9H, piperazine and CHN), 3.08 (t, 2H, J ) 7 Hz,
benzyl CH2), 7.20-8.10 (m, 7H, aromatic); GC-MS m/z 366
(M+ + 2, 3), 365 (M+ + 1, 21), 364 (M+, 74), 321 (41), 254 (21),
181 (100), 141 (35), 111 (22). Anal. (C25H36N2‚2HCl) C, H, N.
Ra d ioliga n d Bin d in g Assa ys. All the procedures followed
to perform the binding assays were previously described. The
σ1 and σ2 receptor binding determinations were carried out
according to the method of Matsumoto et al.55 Dopamine D2-
like receptor binding was carried out according to the work of
Briley and Langer.56 Adrenergic R1 receptor binding was
carried out according to the method of Glossmann and Hor-
nung,57 and serotonin 5-HT3 receptors binding was determined
according to Hall et al.58 The radioligands (+)-[3H]pentazocine,
[3H]DTG, [3H]spiroperidol, [3H]prazosin, and [3H]granisetron
were purchased from Perkin-Elmer Life Sciences (Zaventem,
Belgium). Male Dunkin guinea pigs and Wistar Hannover rats
(250-300 g) were from Harlan, Italy.
Gu in ea P ig Bla d d er F u n ction a l Assa y. The activity
evaluation of σ2 receptor ligands in electrically stimulated
guinea pig bladder was performed according to the work of
Colabufo et al.39 Guinea pigs (200-300 g) were killed by
decapitation and their bladders were removed and quickly
washed in Krebs solution (118 mM NaCl, 4.75 mM KCl, 2.45
mM CaCl2, 1.71 mM MgCl2, 25.0 mM NaHCO3, 0.93 mM KH2-
PO4, 11.0 mM glucose). The detrusor strip section was placed
in 20 mL organ baths containing Krebs solution bubbled with
5% CO2 and 95% O2 gas at 37.0 °C. The strips were placed
under a 1 g load, and contractility was measured using Fort
10 transducers original WPI, connected to a PowerLab 4/20
ADInstrument recorder. To the Krebs solution were added 1
µM atropine to mask muscarinic receptors; 1 µM indomethacin,
as a cyclooxygenase inhibitor; and 1 µM ketanserin to mask
5-HT2 serotonin receptors. The desensitization of σ1 receptors
was obtained by equilibrating the tissue for 75 min with 5 µM
(+)-pentazocine and replacing every 15 min the dressed
solution. Using Krebs solution without (+)-pentazocine, the
tissue was washed and then stimulated at 2.0 Hz using a
Panlab Digital Stimulator Letica 12106 at 150 mA, 1 ms in
duration with longitudinally platinum electrodes positioned
in the organ bath. Following a 90-120 min equilibrium period,
during which the Krebs solution was changed several times,
test compounds were administrated in a cumulative dose,
[m, 6H, cyclohexyl (CH2)3], 1.51-1.72 (m, 6H, CHCH2CH2CH2
and cyclohexyl 2 CH2), 1.78-1.88 [m, 4H, endo (CH2)2], 1.90-
2.00 (m, 2H, eso CHCH2), 2.33-2.48 (m, 3H, CHN and CH2N),
2.52-2.88 (m, 11H, piperazine and benzylic), 3.78 (s, 3H,
OCH3), 6.58-7.10 (m, 3H, aromatic); GC-MS m/z 372 (M+
+
2, 3), 371 (M+ + 1, 23), 370 (M+, 79), 327 (23), 260 (31), 181
(100), 161 (21), 112 (23). Anal. (C24H38N2O‚2HCl) C, H, N.
1-Cycloh exyl-4-[4-(1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-
1
bu tyl]p ip er a zin e (36): H NMR δ 1.00-1.31 [m, 6H, cyclo-
hexyl (CH2)3], 1.38-2.10 [m, 14H, (CH2)2CH(CH2)3 and cyclo-
hexyl 2 CH2], 2.11-2.80 (m, 14H, piperazine, benzylic, CHN
and CH2N), 6.80-7.21 (m, 4H, aromatic); GC-MS m/z 356 (M+
+ 2, 2), 355 (M+ + 1, 18), 354 (M+, 61), 311 (41), 244 (24), 181
(100), 111 (21). Anal. (C24H38N2‚2HCl) C, H, N.
1-Cycloh exyl-4-[4-(5-m eth oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)bu tyl]p ip er a zin e (37): 1H NMR δ 1.01-1.21 [m,
6H, cyclohexyl (CH2)3], 1.23-1.95 [m, 14H, (CH2)2CH(CH2)3
and cyclohexyl 2 CH2], 2.21-2.30 (m, 1H, CHN), 2.33 (t, 2H,
J ) 8 Hz, CH2N), 2.38-2.75 (m, 11H, piperazine and benzylic),
3.78 (s, 3H, OCH3), 6.65-7.05 (m, 3H, aromatic); GC-MS m/z
386 (M+ + 2, 2), 385 (M+ + 1, 18), 384 (M+, 61), 341 (31), 274
(31), 181 (100). Anal. (C25H40N2O‚2HCl) C, H, N.
1-Cycloh exyl-4-[5-(1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-
p en tyl]p ip er a zin e (38): 1H NMR δ 1.00-1.89 [m, 20H,
cyclohexyl (CH2)5 and (CH2)2CHCH2(CH2)3], 1.90-2.10 (m, 2H,
CHCH2), 2.41 (t, 2H, J ) 8 Hz, CH2N), 2.50-3.01 (m, 12H,
piperazine, benzylic and CHN), 6.90-7.15 (m, 4H, aromatic);
GC-MS m/z 370 (M+ + 2, 1), 369 (M+ + 1, 18), 368 (M+, 61),
325 (35), 237 (44), 181 (100), 131 (25), 111 (24). Anal.
(C25H40N2‚2HCl‚1/4H2O) C, H, N.
1-Cycloh exyl-4-[5-(5-m eth oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)p en tyl]p ip er a zin e (39): 1H NMR δ 1.12-1.85
[m, 22H, cyclohexyl (CH2)5 and (CH2)2CH(CH2)4], 2.21-2.39
(m, 3H, CHN and CH2N), 2.41-2.75 (m, 11H, piperazine and
benzylic), 3.78 (s, 3H, OCH3), 6.65-7.05 (m, 3H, aromatic);
GC-MS m/z 400 (M+ + 2, 3), 399 (M+ + 1, 23), 398 (M+, 75),
355 (32), 237 (54), 181 (100). Anal. (C26H42N2O‚2HCl) C, H,
N.
1-Cycloh exyl-4-[6-(5-m eth oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)h exyl]p ip er a zin e (40): 1H NMR δ 1.11-2.15 [m,
24H, cyclohexyl (CH2)5 and (CH2)2CH(CH2)5], 2.23-2.38 (m,
3H, CH2N and CHN), 2.41-2.82 (m, 11H, piperazine and
benzylic), 3.80 (s, 3H, OCH3), 6.65-7.11 (m, 3H, aromatic);
GC-MS m/z 414 (M+ + 2, 3), 413 (M++ 1, 17), 412 (M+, 58),
369 (27), 251 (30), 181 (100). Anal. (C27H44N2O‚2HCl) C, H,
N.
1-Cycloh exyl-4-[3-(5-h yd r oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)p r op yl]p ip er a zin e (41). Compound 33 (0.37 g,
1.0 mmol) was refluxed in 48% HBr (25 mL) for 12 h under
stirring. After cooling, the mixture was washed with 6N KOH
and extracted three times with CH2Cl2. The collected organic
layers were dried and evaporated under reduced pressure to
afford an oily residue which was purified by chromatography
to afford the target compound: 1H NMR δ 1.05-1.28 [m, 6H,
cyclohexyl (CH2)3], 1.45-1.95 [m, 12H, (CH2)2CH(CH2)2 and
cyclohexyl 2 CH2], 2.21-2.48 (m, 3H, benzylic), 2.50-2.80 (m,
11H, piperazine, CH2N and CHN), 4.80-5.40 (broad s, 1H, OH,
D2O exchanged), 6.60-7.05 (m, 3H, aromatic); GC-MS m/z
357 (M+ + 1, 13), 356 (M+, 51), 313 (26), 181 (100). Anal.
(C23H36N2O‚2HCl‚H2O) C, H, N.
1-Cycloh exyl-4-[3-(6-h yd r oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)p r op yl]p ip er a zin e (42). A solution of BBr3 (0.12
mL, 1.3 mmol) in anhydrous CH2Cl2 was added dropwise to a
solution of compound 34 (0.50 g, 1.35 mmol) in the same
solvent cooled at -78 °C under N2. The mixture was stirred
overnight and allowed to reach room temperature. After
cooling, the reaction was quenched with H2O and then with a
solution of K2CO3. The resulting mixture was extracted with
CH2Cl2. The organic layers were collected, dried over Na2SO4,
and then concentrated to dryness to afford a brown yellow
solid. Purification by crystallization from diethyl ether gave
the title compound: 1H NMR δ 1.18-1.38 [m, 6H, cyclohexyl
(CH2)3], 1.54-2.00 [m, 12H, cyclohexyl 2 CH2, (CH2)2CH-