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ADN-1184 a monoaminergic ligand with 5-HT6/7 receptor antagonism: pharmacological profile and potential therapeutic utility.

Kołaczkowski M, Mierzejewski P, Bieńkowski P, Wesołowska A, Newman-Tancredi A.
Br J Pharmacol. 2013 Nov 6. doi: 10.1111/bph.12509. [Epub ahead of print]

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 treatment of BPSD.
EXPERIMENTAL APPROACH: 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.
KEY RESULTS: 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 (CAR) (MED = 3 mg/kg i.p.). Remarkably, ADN-1184 also reduced immobility time in the forced swim test at low doses (0.3 and 1 mg/kg i.p.; higher doses were not significantly active). Notably, up to 30 mg/kg 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 i.p.).
CONCLUSIONS AND IMPLICATIONS: ADN-1184 combines antipsychotic-like with antidepressant-like properties without interfering with memory function or locomotion. This profile is superior to that of commonly-used atypical antipsychotics tested under the same conditions (Kołaczkowski et al., submitted) and suggests that it is feasible to identify drugs that improve behavioural and psychological symptoms without exacerbating cognitive deficit or movement impairment which are of particular concern in dementia patients.