Pan European Networks - Horizon 2020 - page 51

complex etiologies such as central nervous system (CNS)
diseases. Indeed, a promising strategy to identify novel
pharmacotherapeutics is the discovery of designed multiple
ligands (DML) that interact with two or more biological targets that
are physiologically relevant for the disease. This approach is
focused on rationally designed ligands that act selectively on
multiple targets while avoiding side effects characteristic of ‘dirty’,
non-selective molecules. Many currently available antipsychotics
used off-label for BPSD, such as clozapine or olanzapine, are
examples of multi-target agents, although they were not rationally
designed to be so.
As a consequence of not being designed, these drugs cause
numerous side effects which are related to poor selectivity and an
affinity to off-targets. For instance, affinity of most antipsychotics
to histaminic receptors is responsible for sedation, blockade of
hERG channel inducing QT prolongation/arrhythmia, and
blockade of muscarinic receptors causes dry-mouth, urinary
retention and constipation. In contrast, DMLs are created to act
selectively on multiple targets of therapeutic interest while
avoiding dangerous interactions with off-targets related to serious
side effects.
The ‘5-HT6 plus’ platform to fight BPSD
During the past six years we have discovered a series of promising
drug candidates with a favourable pharmacological profile aimed
at treating BPSD. Our previous studies have resulted in
identification of chemical series of multimodal monoamine
modulators with 5-HT6 serotonin receptor (5-HT6R) antagonism
as a common denominator. Those compounds possess promising
activity, with efficacy and safety profiles in accordance with those
desired for the modern treatment of BPSD, because:
1) The compounds are based on a mechanism of action that has
been positively validated by studies on cognitive processes –
vide positive results of recent phase two proof-of-concept
studies of selective 5-HT6R antagonists;
2) The compounds associate 5-HT6R antagonism with beneficial
interaction at other targets, including 5-HT2A, 5-HT7 or D2
receptors and/or serotonin transporter (SERT), which are proven
to be involved in control of psychoses and mood disorders;
3) Our previous studies show that drug candidates with such a
mechanism of action display the desired combination of
efficacy and safety properties in preclinical studies, in contrast
to currently available drugs tested in the same conditions; and
4) The designed combination of receptor activities achieves
superior results in pharmacological studies than reference
selective ligands acting only at individual receptors.
The intellectual property resulting from this programme was
covered by five international and five Polish patent applications.
Among them, we have discovered a series of promising drug
candidates with a favourable pharmacological profile aimed at
treatment of BPSD.
Who are we?
We are a group of medicinal chemists specialising in
in silico-
supported drug design and discovery, focusing on CNS disorders,
especially psychotic, affective and cognitive disturbances.We
created a strong network of collaborations with scientific groups to
cover a drug discovery process from
in silico-
supported drug
design, through chemical synthesis and broad
in vitro
screening,
to advanced animal models of CNS disorders (for more
information check:
We seek collaborations compatible with our competences to
broaden the range of capabilities and create a strong
consortium concerning:
n
Synthetic chemists;
n
Pk studies;
n
Brain electrophysiology;
n
Brain microdialysis;
n
Aged animals;
n
Genetic models of neurodegenerative diseases; and
n
Intracellular signalling.
H O R I Z O N 2 0 2 0 P R O J E C T S : P O R TA L
I S S U E S I X
51
P R O F I L E
N E U R O D E G E N E R AT I O N
Marcin Kołaczkowski, PhD
Assistant Professor
Faculty of Pharmacy
Jagiellonian University Medical College
tel :
+48 12 620-54-60
1...,41,42,43,44,45,46,47,48,49,50 52,53,54,55,56,57,58,59,60,61,...244
Powered by FlippingBook