5-ht6 antagonist/d2 partial agonist targeting behavioural and psychological symptoms of dementia
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Novel 5-HT6 receptor antagonists/ D2 receptor partial agonists targeting behavioral and
psychological symptoms of dementia (BPSD)
Monika Marcinkowska,1 Adam Bucki,1 Maciej Pawłowski,1 Anna Wesołowska,1Paweł Mierzejewski,2 Przemysław Bieńkowski2
and Marcin Kołaczkowski1,3
1Jagiellonian University, Medical College, Cracow, Poland;2Institute of Psychiatry and Neurology, Warsaw, Poland
3Adamed Ltd., Pieńków, Poland
Dementia is much more than forgetting…
Cognitivedecline
Behavioral and psychological symptoms (BPSD)
Social withdrawal
Aggression
Agitation
Psychosis
Depression
Anxiety
The risk of BPSD in dementia patients approaches 90%1
[1] Iwasaki, K.; Satoh-Nakagawa, T. et al. J. Clin Psychiatry 2005, 66, 248-252
Current therapeutic strategies are far from ideal…
• Behavioral symptoms are treated off label with atypical antypsychotics
However: • This therapy displays only modest efficacy, • Cause further cognitive decline and serious side effects
There is a need for a more effective and safe therapy,dedicated for BPSD
Cognitivedecline
Behavioral and psychological symptoms (BPSD)
Cognitive decline
Molecular targets
5-HT6 antagonists2
+ Procognitive effects in humans
+ Moderate antidepressant and anxiolytic effects in animals
D2 partial agonists3
+ Promising anxiolytic\antidepressant activity\ antipsychotic\antiparkinsonian effects
- No procognitive effects in dementia patients
Multimodal approach may combine the strengths of both groups
+ Enhancement of antidepressant and anxiolytic activity – proven synergy in animal models+ Introduction of pro-cognitive effect
[2] Wesołowska, A., Pharmacol Rep, 2010, 62, 564-577 [3] Burda, K. et al Pharmacol Rep. 2011, 63, 898-907
Design of innovative hybrid molecules
5-HT6 receptor antagonist D2 receptor partial agonist
‘Merged’ pharmacophores resulting in dually acting 5-HT6/ D2 hybrid molecule
5-HT6 fragment
D2 fragment
SB-271046
Aripiprazole
Library of hybrid molecules
5-HT6 fragment
D2 fragment
n = 1, 2
In vitro assays
5-HT6 fragment
D2 fragment
Compound 14 is the most promising 4
Target pKi pEC50(ago)
pKB(anta)
5-HT6 9.52 - 8.77
D2 8.49 7.51 8.59
5-HT1A 8.41 - 7.55
M3 ~5 - -
H1 ~7 - -
hERG ~5 - -
[4] The series was protected by a world patent application WO13_001499
In vitro profile of 14
Affinity for targets that improve cognition and mood 5-HT6, D2, 5-HT1A
Negligible affinity for targets associated with side-effects H1, M1, hERG
In vivo activity
Compound 14 shows significant improvement of antidepressant and anxiolytic activity in rats, comparing to selective 5-HT6 antagonist or D2 partial agonist.
Test proceduresCompound 14 SB-271046 Aripiprazole
MED mg/kg
ANTIDEPRESANT ACTIVITY:
Porsolt's forced swim test in rats 1 10 3
Saccharin Self-Administration in rats 1 - -
ANXIOLYTIC ACTIVITY:
Vogel's conflict drinking test in rats 1 3 10
Elevated plus maze test in rats 0.03 10 3
Summary
• We designed a library of hybrid molecules acting as 5-HT6 antagonists/D2 partial agonists
• Compound 14 shows significant antidepressant and anxiolytic activity in rats, which makes it suitable for further evaluation regarding BPSD
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