ADN‐1184 a monoaminergic ligand with 5‐HT_6/7 receptor antagonist activity: pharmacological profile and potential therapeutic utility

Abstract

BACKGROUND AND PURPOSEMany 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. EXPERIMENTAL APPROACHWe 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 RESULTSADN-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 IMPLICATIONSADN-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. AbbreviationsAD, Alzheimer's disease; BPSD, behavioural and psychological symptoms of

ADN-1184, a monoaminergic ligand with 5-HT6/7 receptor antagonist action, exhibits activity in animal models of anxiety

“…ADN-1184, a novel monoaminergic ligand with antipsychotic and antidepressant activities (Kołaczkowski et al 2014a ), possesses a multitarget profile distinct from current atypical antipsychotic agents. Its dopamine D 2 and D 3 antagonist properties, together with its potent blockade of 5-HT 6 , 5-HT 7 and 5-HT 2A receptors, and the absence of anticholinergic and antihistaminic effects, are consistent with a beneficial influence on psychosis, cognition, and mood impairments.…”

“…In Kołaczkowski et al ( 2014a ), we described a novel arylsulfonamide derivative (ADN-1184) that possesses a preclinical profile of activity corresponding to criteria required for treatment of both psychosis and depressive symptoms of BPSD without exacerbating cognitive impairment or inducing motor disturbances. As no animal model of BPSD is available, ADN-1184’s potential antipsychotic properties have been evaluated in a range of procedures, including hyperactivity and stereotypies induced by MK-801, procedures relevant to dementia patients who suffer from psychoses of glutamatergic origin (Bardin et al 2007 ; Siegel 1978 ) as well as conditioned avoidance response (Kołaczkowski et al 2014a ). In all these models, ADN-1184 demonstrated an antipsychotic-like potency similar to or even stronger than that produced by SGAs and tested in the same experimental conditions (Kołaczkowski et al 2014a ).…”

“…As no animal model of BPSD is available, ADN-1184’s potential antipsychotic properties have been evaluated in a range of procedures, including hyperactivity and stereotypies induced by MK-801, procedures relevant to dementia patients who suffer from psychoses of glutamatergic origin (Bardin et al 2007 ; Siegel 1978 ) as well as conditioned avoidance response (Kołaczkowski et al 2014a ). In all these models, ADN-1184 demonstrated an antipsychotic-like potency similar to or even stronger than that produced by SGAs and tested in the same experimental conditions (Kołaczkowski et al 2014a ). Moreover, ADN-1184 was also active in a classic model of potential antidepressant activity—the forced swim test—showing potency of the same order of magnitude as that of imipramine.…”

“…While being active in models of psychosis, mood deficit and memory performance, ADN-1184 additionally did not elicit catalepsy or a decrease in locomotor activity when administered at antipsychotic and antidepressant doses. ADN-1184 only began to decrease locomotor action at a dose of 30 mg/kg and, at the same dose, weakly elicited catalepsy (Kołaczkowski et al 2014a ).…”

Multifunctional arylsulfonamide derivatives with 5-HT6/5-HT7 receptor antagonistic activity: a structural study

“…All the presented compounds display antagonistic properties towards all the abovementioned targets. Compound (I) (work symbol ADN1184) was broadly studied for its pharmacological profile (Kołaczkowski et al, 2014b) and activity in animal models of anxiety (Partyka et al, 2016).…”