Novel antagonists of 5-HT6 and/or 5-HT7 receptors affect the brain monoamines metabolism and enhance the anti-immobility activity of different antidepressants in rats.
3区 · 心理学
作者: Anna Partyka ; Magdalena Jastrzębska-Więsek ; Lucyna Antkiewicz-Michaluk ; Jerzy Michaluk ; Agnieszka Wąsik ; Vittorio Canale ; Paweł Zajdel ; Marcin Kołaczkowski ; Anna Wesołowska
The aim of the present study was to investigate and compare the ability of three novel 5-HT6 and/or 5-HT7 receptor antagonists as follows: PZ-668-a preferential 5-HT6 antagonist; PZ-1433-a preferential 5-HT7 antagonist; and ADN-1184-a monoaminergic ligand with potent 5HT6/7 antagonist properties, to augment the effect of antidepressant drugs with different mechanisms of action (escitalopram, reboxetine, and bupropion) in the forced swim test in rats. In neurochemical ex vivo experiments, the influence of the tested compounds on levels of monoamines and their metabolites were determined in the rat frontal cortex, in addition to behavioral experiments. The results of our investigations revealed the differences in action of the tested compounds. PZ-668 strongly affected dopaminergic and faintly noradrenergic system, PZ-1433 induced a significant elevation in dopamine, noradrenaline, serotonin, and their metabolite levels, while ADN-1184 appeared to act mostly through dopaminergic transmission. The agent with 5-HT6 antagonistic properties (PZ-668) revealed an anti-immobility action of bupropion (primarily) and reboxetine in interaction studies. PZ-1433, the 5-HT7 preferential antagonist facilitated antidepressant effects of escitalopram and, to a lesser extent, bupropion, while ADN-1184, a multireceptor ligand, potentiated the effectiveness of escitalopram, reboxetine, and bupropion. The presented findings may contribute to further investigations of more effective and safer antidepressant drugs, and may help selecting optimal augmentation therapy in treatment-resistant depression.
2016-06-01·Naunyn-Schmiedeberg's Archives of Pharmacology4区 · 医学
ADN-1184, a monoaminergic ligand with 5-HT6/7 receptor antagonist action, exhibits activity in animal models of anxiety
4区 · 医学
作者: Partyka, Anna ; Wasik, Anna ; Jastrzebska-Wiesek, Magdalena ; Mierzejewski, Pawel ; Bienkowski, Przemyslaw ; Kolaczkowski, Marcin ; Wesolowska, Anna
Behavioral and psychological symptoms of dementia (BPSD) include apathy, sleep problems, irritability, wandering, elation, agitation/aggression, and mood disorders such as depression and/or anxiety. Elderly patients are usually treated with second-generation antipsychotics; however, they present not enough efficacy against all symptoms observed. Hence, there still is an unmet need for novel pharmacotherapeutic agents targeted BPSD. A novel arylsulfonamide derivative ADN-1184 has been developed 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. To broaden its pharmacological efficacy toward anxiety symptoms, its anxiolytic properties have been examined in common animal preclinical models in rats and mice. ADN-1184 significantly increased the number of entries into open arms measured in the elevated plus-maze test; however, it simultaneously increased parameters of exploratory activity. In the Vogel conflict drinking test, ADN-1184 dose-dependently and significantly increased the number of shocks accepted and the number of licks. Moreover, in mice, it also had specific anxiolytic-like activity in the four-plate test, and only negligible one at a specific mid-range dose measured in the spontaneous marble burying test. The obtained findings reveal that ADN-1184 displays anxiolytic-like activity in animal models of anxiety which employed punished stimuli. In its unusual combination of some anxiolytic action with already proven antipsychotic and antidepressant properties, and lack of any disruptive impact on learning and memory processes and motor coordination, ADN-1184 displays a profile that would be desired for a novel therapeutic for BPSD.
2014-02-01·British Journal of Pharmacology2区 · 医学
ADN-1184 a monoaminergic ligand with 5-HT6/7 receptor antagonist activity: pharmacological profile and potential therapeutic utility
2区 · 医学
作者: Kolaczkowski, M. ; Mierzejewski, P. ; Bienkowski, P. ; Wesolowska, A. ; Newman-Tancredi, A.
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.