Á.A. Kelemen et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxx–xxx
Scheme 2. Synthesis of aryl-piperidine (11–12),
and 5,6-dihydropyridine (13), and phenoxy (15)
analogues. Reagents and conditions: (A) 2-bro-
moethanol, K2CO3, MeCN, RT, overnight; (B)
MsCl, TEA, DCM, reflux, 2 h; (C) tryptoline/tetra-
hydro-β-carboline, K2CO3, MeCN, reflux, over-
night; (D) NBS, cc. AcOH, THF, water, 1.5 h, 0 °C.
Scheme 3. Synthetic route leading to the amide-analogue (16). Reagents and conditions: (A) HATU, DIPEA, DMF, RT, overnight; (B) MsCl, TEA, DCM, reflux, 2 h; (C)
tryptoline/tetrahydro-β-carboline, K2CO3, MeCN, reflux, overnight; (D) NBS, cc. AcOH, THF, water, 1.5 h, 0 °C.
The synthesis of the aryl-piperidine 11–12, the 5,6-dihydro-pyridine
13, and the phenoxy 15 analogues (Scheme 2) was also started from the
corresponding secondary amines 21a–d, followed by the alkylation
with 2-bromoethanol, to afford the alcohols 22a–d. The crude mesy-
lated derivatives 23a–d were then used for alkylation of the tetrahydro-
β-carboline to get 24a–d that was spirocyclized to 11, 12, 13, 15, re-
spectively.
1-(2-Hydroxyethyl)piperazine (25) was used as starting material for
acylation22 of 25 with the 4-chlorobenzoic acid 26 gave the corre-
sponding amide 27, which was treated with mesyl-chloride to yield the
mesylate 28. After the alkylation of tetrahydro-β-carboline with 28, the
spirocyclization of intermediate 29 afforded 16.
HT7R. Selectivity against 5-HT1AR decreased, however the selectivity
against the 5-HT2AR subtype has improved. 6 showed lower selectivity
(65.6-fold) towards 5-HT6R than 7 (163.3-fold).
Starting from the most active 4-fluorine derivative (14) the 5,6-di-
hydropyridine derivative (13) showed decreased selectivity (91.8-fold)
against 5-HT1AR. Replacing the piperazine ring by piperidine (12) gave
10-times lower affinity that was further confirmed by the corresponding
4-chloro analogue (11). Selectivities against 5-HT1AR and 5-HT2AR did
not change significantly, but the 5-HT6R selectivity decreased ten-
times. Similar to 11 and 12, introduction of the phenoxy-piperidine
moiety (15) improved the affinity towards 5-HT6R. Finally, the ben-
zoyl-piperazine derivative (16) showed reduced affinity to 5-HT7R,
however, it has the highest selectivity against 5-HT2AR (32.8-fold).
In summary, preliminary SAR data demonstrates that spiro[pyrro-
lidine-3,3′-oxindoles] are potent and selective 5-HT7R ligands. We
confirmed that the 2-methylene linker ensures the ideal distance be-
tween HYD1 and HYD2 and therefore it is beneficial for the 5-HT7R
affinity. Although previous findings13,23 suggested that the para sub-
stitution at the aryl-piperazine moiety may abolish 5-HT7R affinity we
showed that it provides spiro[pyrrolidine-3,3′-oxindoles] with reason-
able affinity and selectivity against 5-HT1AR and 5-HT6R. Actually, the
4-fluoro analogue (14) showed the best affinity and most remarkable
The synthesized compounds were investigated in competition
binding assays against 5-HT7R and other closely related serotonin re-
ceptor subtypes 5-HT1AR, 5-HT2AR and 5-HT6R (Table 1).
The unsubstituted phenylpiperazine derivative 7 of the spiro[pyr-
rolidine-3,3′-oxindole] core showed reasonably high affinity towards
the target, however its selectivity was moderate. Halo-scan around the
phenyl ring revealed that the 5-HT7R affinity and 5-HT1A and 5-HT6R
selectivities are increasing from ortho 9 – meta 8 – para 5 direction. In
fact, the para-Cl derivate (5) showed low nanomolar affinity for the
target and more than hundred-fold selectivity against two of the three
other serotonin receptors. Selectivity against these receptors was fur-
ther improved for the para-F analogue 14. As compared to compound 5,
the longer ([CH2]3) alkyl chain in 6 increased the distance between the
PI and HBA features, accounting for an overall loss of affinity for the 5-
selectivity against 5-HT1AR and 5-HT6R. Selectivity against 5-HT2A
R
might be improved by replacing the phenyl substituent of the piper-
azine by a benzoyl group. The present results show the potential of this
novel chemotype and validate its further optimization for more detailed
in vivo characterization in diseases models.
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