ADN-1184 a monoaminergic ligand with 5-HT6/7 receptor antagonist activity: pharmacological profile and potential therapeutic utility
Version of Record online: 24 JAN 2014
© 2013 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Midkine. Guest Editors: Takashi Muramatsu and Kenji Kadomatsu
Volume 171, Issue 4, pages 973–984, February 2014
How to Cite
Kołaczkowski, M., Mierzejewski, P., Bieńkowski, P., Wesołowska, A. and Newman-Tancredi, A. (2014), ADN-1184 a monoaminergic ligand with 5-HT6/7 receptor antagonist activity: pharmacological profile and potential therapeutic utility. British Journal of Pharmacology, 171: 973–984. doi: 10.1111/bph.12509
- Issue online: 24 JAN 2014
- Version of Record online: 24 JAN 2014
- Accepted manuscript online: 6 NOV 2013 11:30PM EST
- Manuscript Accepted: 31 OCT 2013
- Manuscript Revised: 17 OCT 2013
- Manuscript Received: 2 JUL 2013
- Adamed Ltd.
- National Centre for Research and Development (NCBR). Grant Number: KB/88/12655/IT1-C/U/08
- behavioural pharmacology
Background and Purpose
Many dementia patients exhibit behavioural and psychological symptoms (BPSD) that include psychosis, aggressivity, depression and anxiety. Antipsychotic drugs are frequently prescribed but fail to significantly attenuate mood deficits, may interfere with cognitive function and are associated with motor and cardiac side effects, which are problematic in elderly patients. A need therefore exists for drugs that are better suited for the treatment of BPSD.
We used in vitro cellular and in vivo behavioural tests to characterize ADN-1184, a novel arylsulfonamide ligand with potential utility for treatment of BPSD.
ADN-1184 exhibits substantial 5-HT6/5-HT7/5-HT2A/D2 receptor affinity and antagonist properties in vitro. In tests of antipsychotic-like activity, it reversed MK-801-induced hyperactivity and stereotypies and inhibited conditioned avoidance response (MED = 3 mg·kg−1 i.p.). Remarkably, ADN-1184 also reduced immobility time in the forced swim test at low doses (0.3 and 1 mg·kg−1 i.p.; higher doses were not significantly active). Notably, up to 30 mg·kg−1 ADN-1184 did not impair memory performance in the passive avoidance test or elicit significant catalepsy and only modestly inhibited spontaneous locomotor activity (MED = 30 mg·kg−1 i.p.).
Conclusions and Implications
ADN-1184 combines antipsychotic-like with antidepressant-like properties without interfering with memory function or locomotion. This profile is better than that of commonly used atypical antipsychotics tested under the same conditions and suggests that it is feasible to identify drugs that improve BPSD, without exacerbating cognitive deficit or movement impairment, which are of particular concern in patients with dementia.