ADN-1184, a monoaminergic ligand with 5-HT_{6/7} receptor antagonist action, exhibits activity in animal models of anxiety

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

Study of a mechanism responsible for potential antidepressant activity of EMD 386088, a 5-HT_6 partial agonist in rats

It was shown that 5-HT(6) receptor agonists can exert pharmacological activity due to various modifications in monoamines’ level and metabolism activity in rats’ brain structures. This finding was correlated with antidepressant- or anxiolytic-like properties of these compounds. The study was designed to establish a possible mechanism of the antidepressant-like activity of the partial 5-HT(6) receptor agonist EMD386088 (5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole hydrochloride) in rats. The concentrations of monoamines (dopamine (DA), noradrenaline (NA), and serotonin (5-HT)) and the rate of their metabolism were measured ex vivo in the brain structures (hippocampus, nucleus accumbens, striatum) using high-performance liquid chromatography (HPLC). The rats were killed after the forced swim test (FST); the collected tissue samples were used to ex vivo experiments. The potency of EMD386088 to blockade dopamine transporter (DAT) was tested in a functional in vitro study. FST was used to assess the involvement of D(1)- and D(2)-like receptor subfamilies in antidepressant-like properties of EMD386088. Neurochemical data from ex vivo experiments showed that antiimmobility activity of EMD386088 may be connected with the activation of dopaminergic system, while neither noradrenergic nor serotonergic ones are involved in its effect. EMD386088 also possesses a significant affinity for DAT which may be a mechanism in the abovementioned effect. Behavioral data seem to confirm the importance of dopaminergic system activation in antidepressant-like activity of EMD386088, since this effect, observed in the FST, was abolished by the preferential D(1)- and D(2)-like receptor subfamily antagonists SCH23390 and sulpiride, respectively. Dopaminergic system is involved in antidepressant-like activity of EMD386088

Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1A receptor partial agonists

Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Serotonin 5-HT1A receptor is considered as an interesting target of antidepressant therapy. In the present study, the intrinsic activity at different signaling pathways coupled to serotonin 5-HT1A receptor, antidepressant-like and pharmacokinetic properties, and the safety profile of two novel imidazopurine-2,4-dione derivatives, namely compounds AZ-853 (8-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-1,3-dimethyl-1H- imidazo[2,1-f]purine-2,4(3H,8H)-dione) and AZ-861 (1,3-dimethyl-8-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), were studied in animal models through in vitro and in vivo experiments. We demonstrated that AZ-853 and AZ-861, which structurally differ by one substituent and its placement in the phenyl ring, showed varied functional, pharmacological, and pharmacokinetic properties as well as side effect profiles. AZ-861 exhibited stronger agonistic action in all functional assays. After acute and repeated administration in mice, both compounds showed antidepressant-like activity in the forced swim test, which was partially mediated by 5-HT1A receptor activation. AZ-853 showed a more potent antidepressant-like effect, presumably due to its better penetration into brain structures. Both compounds did not show anticholinergic properties, but after repeated administration, they induced weak sedation and lipid metabolism disturbances without affecting serum glucose level. The stronger α1-adrenolytic effect of AZ-853 is responsible for decreased systolic blood pressure, and in contrast to AZ-861, AZ-853 induced weight gain in mice. The interesting comparative pharmacological profiles of AZ-853 and AZ-861 encourage to conduct further experiments to fully understand their mechanisms and differences in action

The 1,3,5-triazine derivatives as innovative chemical family of 5-HT6 serotonin receptor agents with therapeutic perspectives for cognitive impairment

Among serotonin receptors, the 5-HT6 subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HT6R ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient “druglikeness” properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family of potent 5-HT6R ligands. For the most active triazine 5-HT6R agents found (1-4), a wider binding profile and comprehensive in vitro evaluation of their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were investigated within this work. Results indicated the most promising pharmacological/druglikeness profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) and 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (4), which displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative (4) seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and non-sulfone structure with the best 5-HT6R binding properties

Monitoring of tacrolimus concentration after kidney or heart transplantation - the importance of intra-subject variability parameters

Background. Properly managed immunosuppression in post-transplant therapy is a necessary for minimizing the risk of organ rejection. Aim of the study. Steady-state tacrolimus (TAC) trough concentration (Cssmin) analysis in the first month following heart or kidney transplantation. The intra-individual coefficient of variation (CV) was calculated, correlations with biochemical parameters were searched and recommendations/current guidelines for optimizing TAC dosing based on evidence-based medical databases (EBM) were presented. Material and methods. 24 patients aged 24-79 years (mean 47,1±13,9 years) were selected for retrospective analysis; 12 after heart transplant and 12 after kidney transplant. TAC dosing was the same in the patient groups and did not change during the analysis (first month); in heart recipients it was 2 mg/day and 1 mg/day in kidney recipients. Whole blood Cssmin TAC (steady state) was measured four times in all patients; the first in the 15th day of treatment, the second in 16-18, the third in 17-19, the fourth in 18-21. The QMS Tacrolimus immunoassay was used to analyze TAC concentration using the Indiko Plus automated chemistry analyzer. Results. The median Cssmin TAC value was 6,9-15,6 ng/mL after heart transplant and 8,7-16,0 ng/mL after kidney transplant. The CV range of patients after heart transplantation was 4-60%, while after kidney transplantation it was 8-40%. CV>30% (a higher risk of acute rejection) after heart transplant concerned 25% of patients and 15% after kidney transplant. The analysis of organ survival in heart and kidney recipients showed 83% and 100%, respectively, at an average of 2,7±0,5 and 3,25±2,5 years after transplantation. There were no significant correlations (p>0,05) between CV and selected biochemical parameters. Conclusion. CV>30% may indicate a large variability in the pharmacokinetics of TAC and thus, the need to optimize the dosage/physiological parameters affecting its concentration values. It seems necessary to improve the personalization of immunosuppressive therapy with TAC, taking into account individual parameters of extra- and intra-individual variability, in order to obtain better therapeutic results and avoid acute/chronic rejection, accelerated in time of organ transplant loss and/or the occurrence of additional side effects of TAC