Report No xxxx - Instytut Fizyki JÄ drowej PAN

1 H, 13 C NMR AND GIAO/DFT CALCULATIONS OF SUBSTITUTED
N-(4-ARYL-1-PIPERAZINYLBUTYL) DERIVATIVES,
NEW ANALOGUES OF BUSPIRONE
Maciej Pisklak a , Jerzy Kossakowski b , Iwona Wawer a
a Department of Physical Chemistry, Faculty of Pharmacy, The Medical University
of Warsaw, Banacha 1, 02097 Warsaw, Poland; b Department of Medicinal Chemistry,
The Medical University of Warsaw, Oczki 3, 02007 Warsaw, Poland
Buspirone was a first of the anxiolytics of second generation, with high affinity to
5-HT1A and D2 receptors. The ligands for the 5-HT1A receptors are of special interest since
they may be important in treating psychiatric disorders (anxiety, depressions). Several groups
of ligands have been synthesised and tested for pharmacological activity with the task to find
a compound with better selectivity and higher affinity. Continuing our studies on potential
anxiolytics we have designed a series of compounds, the N-(4-aryl-1-piperazinylbutyl)
derivatives with bulky imide moiety (see the structures with carbon numbering).
2
3
1
11
H
15
R
10
18
14
O
N
16 13
12
H
4 5 17 6
9
8
7
19
20
21
22
N
23
26
24 25
N
R O
13 C NMR spectra of a series of compounds were recorded for CDCl 3 solution and solid state.
NMR shielding constants were calculated using GIAO/DFT approach for selected model
fragment. Reliable assignment of carbon resonances was made with the aid of theoretical
data.
Considering the interaction of a ligand with 5-HT1A receptor, it was supposed that the
distances between the aromatic substituent, nitrogen atom of piperazine and carbonyl group of
imide moiety are important for binding of buspirone-like compounds. Therefore, the data
concerning the structure, conformational flexibility and properties of functional groups are of
interest. Main interest was placed on the configuration of piperazine nitrogen attached to the
aromatic moiety. The combined NMR and theoretical studies enable for improvement of the
model of pharmacophore.
Additionally, little research has been done on solid state structures of buspirone
analogues applying 13 C CP MAS NMR techniques and reasonable assignment of carbon
resonances was made with the aid of theoretical studies.
Ar
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