L. Huang, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127506
was reacted with (6-fluorobenzo[d]isoxazol-3-yl) piperidine to obtain
peridine) and their derivatives for the D2, 5-HT1A and 5-HT2A receptors
(compounds
6–13;
Compound
6
(2,3-di-
HT2A receptors. When the amine moieties were substituted with 3-tri-
fluoromethyl phenylpiperazine, (pyridin-2-yl)piperazine, 2-methox-
yphenylpiperazine and 2-(piperazin-1-yl) pyrimidine, the resulting
compounds 7–10 demonstrated lower affinities for the three receptors.
In addition, the (6-fluorobenzo[d]isoxazol-3-yl) piperidine derivative
11 exhibited high affinities for the three receptors (D2, Ki = 2.1 nM; 5-
HT1A, Ki = 3.5 nM; 5-HT2A, Ki = 7.8 nM, respectively). Replacement of
the (6-fluorobenzo[d]isoxazol-3-yl) piperidine with a (benzo[d]iso-
thiazol-3-yl)piperazine (compound 12) or (benzo[b]thiophen-7-yl)pi-
perazine (compound 13) reduced the affinities for the three receptors.
Therefore, (6-fluorobenzo[d]isoxazol-3-yl) piperidine had greater affi-
nity for the D2, 5-HT1A, and 5-HT2A receptors than the other hetero-
cyclic arylpiperazine (piperidine).
Fig. 1. First-generation and Atypical antipsychotics.
systems,32 for example, disinhibition of GABAergic neurons in the
frontal cortex, regulating the cholinergic and/or glutamatergic systems.
Blocking of the 5-HT6 receptor increases dopamine release in the pre-
frontal cortex, which is critical in cognition and learning and in neu-
and AD.33–35 Therefore, effects on the a2 and 5-HT6 receptors must also
be taken into account.
To assess the SARs of the compounds, the effects of different sub-
stituent group on amide were evaluated by replacing methyl, ethyl or
phenyl on the R2. Compound 14 (ethyl) showed moderate affinity for 5-
HT1A receptor but not the D2 and 5-HT2A receptors (Table 2). Moreover,
compound 15 (phenyl) exhibited lower affinities for all three receptors.
Replacement of R with a methyl or fluorine group yielded the
fluorine derivative compound 16, which had moderate affinity for the
D2, 5-HT1A, and 5-HT2A receptors. Substitution of a methyl (compound
17) on the R of the benzene ring had similar effects on the D2 and 5-
HT2A receptors and a lesser effect on the 5-HT1A receptor.
Heterocyclic and arylpiperazine (piperidine) fragments were se-
lected as the base moieties based on their preferential binding to do-
pamine and serotonin receptors. Next, hybridisation with amine moi-
eties fragments which were developed by open the amide ring of
aripiprazole and introduction of the different amine moieties based on
cariprazine (Fig. 2), and the two pharmacophores connected via flexible
spacer, finally a new class of compounds with heterocyclic or aryl-pi-
perazines (piperidines) pharmacophores linked to the modifiable amide
HT1A, 5-HT2A, H1, 5-HT2C, 5-HT6, noradrenergic α1 and α2 receptors, a
preliminary pharmacological evaluation was conducted. Among these
derivatives, compound 11 exhibited high affinity for the D2, 5-HT1A, 5-
HT2A, 5-HT6, and α2 receptors, and low affinity for the 5-HT2C, H1, and
α1 receptors and hERG channels. In the behaviour study, compound 11
suppressed apomorphine-induced climbing and MK-801-induced hy-
permobility, significantly reduced 1-(2,5-dimethoxy-4-iodophenyl)-2-
aminopropane (DOI) induced head twitching and had a high threshold
for induction of catalepsy. In addition, compound 11 exhibited dose-
dependent suppression the CRA test. Moreover, compound 11 induced
cognitive improvement in a novel object recognition task.
Substitution of the methylene group between the benzene ring and
the amino group (compound 18) dramatically decreased the affinity for
all three receptors compared to compound 11 (Table 2). Specifically,
introduce methyl groups the nitrogen atoms of the amide, compound
19 exhibited good affinities for the three receptors (D2, Ki = 20.6 nM;
5-HT1A, Ki = 21.3 nM; 5-HT2A, Ki = 12.7 nM, respectively).
Changes in the length of the linker between the benzene ring and
the piperidine ring (Table 2) chain shortening (compound 21) and
5-HT2A receptors. Introduction of OH to the carbon chain of compound
24 resulted in moderate affinity for the D2, 5-HT1A, and 5-HT2A re-
ceptors. Hence, chain length is a determinant of binding affinities for
the three receptors. The derivative with a three-carbon chain (com-
pound 11) showed optimum activity. Finally, when the amide was
moved from the 4-position (compound 11) to the 3-position (compound
22), activity was unaffected.
The general strategy used to prepare the target compounds 6–24 is
pounds 4a-4 g were prepared by hydrolysis of compounds 3a-3 g with
sodium hydroxide. Compounds 5a-5 g were prepared from inter-
mediates 4a-4 g by substitution with 1,3-dibromopropane (1,2-di-
bromoethane or 1,4-dibromobutane) in acetone. Finally, compounds
5a-5 g were reacted with a heterocyclic arylpiperazine (piperidine) in
the presence of K2CO3 and a catalytic amount of KI to afford compounds
The SAR analyses indicated that the binding affinities of these
compounds depend on several factors. First, substitution with a 6-
fluorobenzo[d]isoxazol-3-yl)-piperidine group increases affinity for D2,
5-HT1A, and 5-HT2A receptors compared to other aryl piperazines.
Second, substitutions on benzene ring reduce affinity for those re-
ceptors (H > F > CH3). Third, introduction of a methylene group
Fig. 2. Design of amide derivatives.
2