Preliminary evaluation of anticonvulsant activity and neurotoxicity of some 1,4-substituted piperazine derivatives

A series of 1,4-piperazine derivatives was synthesized and evaluated for anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure threshold (ScMet) assays and for neurotoxicity (TOX). The compounds were only moderately effective. The anticonvulsant activity was accompanied by neurotoxicity. 1-[(4-Chlor-3-methylphenoxy)-acetyl]-4-(2-methoxyphenyl)-piperazine was also evaluated in six hertz seizure test (6-Hz) and showed good activity. At the dose of 100 mg/kg b. w. the compound produced 100% protection after 0.5 h without neurotoxic effect

Polimorfizm –A162G genu PON1 jako czynnik ryzyka rozwoju sporadycznej postaci stwardnienia bocznego zanikowego

Background and purpose: Sporadic amyotrophic lateral sclerosis (sALS) is a devastating neurodegenerative disease, which results from complex genetic and environmental interactions. Recent studies have reported an association between several polymorphisms of the PON1 and PON2 genes and risk of sALS. The aim of the present study was to identify an association between the –A162G polymorphism of the promoter region of the human PON1 gene and the risk of sALS in a Polish population. Material and methods: We included 259 patients with a diagnosis of definite or probable sALS (76 bulbar onset, 183 limb onset) and 694 healthy controls matched for age and sex. The diagnosis of ALS was established according to El Escorial criteria. The polymorphism was studied by Single Nucleotide Polymorphism Real-Time Polymerase Chain Reaction analysis. Results: No overall difference in the PON1 –A162G geno - type and allele distribution was seen between cases and controls (all p > 0.05). There was, however, a difference in the A allele frequency when the bulbar onset group was compared to the controls (p = 0.03), but this significance disappeared after the Bonferroni correction. Conclusions: The results did not show that the –A162G polymorphism of the PON1 gene is a risk factor of sALS in a Polish population; it may affect, however, bulbar onset of the disease

Polimorfizm –A162G genu PON1 jako czynnik ryzyka rozwoju sporadycznej postaci stwardnienia bocznego zanikowego

Background and purpose Sporadic amyotrophic lateral sclerosis (sALS) is a devastating neurodegenerative disease, which results from complex genetic and environmental interactions. Recent studies have reported an association between several polymorphisms of the PON1 and PON2 genes and risk of sALS. The aim of the present study was to identify an association between the – A162G polymorphism of the promoter region of the human PON1 gene and the risk of sALS in a Polish population. Material and methods We included 259 patients with a diagnosis of definite or probable sALS (76 bulbar onset, 183 limb onset) and 694 healthy controls matched for age and sex. The diagnosis of ALS was established according to El Escorial criteria. The polymorphism was studied by Single Nucleotide Polymorphism Real-Time Polymerase Chain Reaction analysis. Results No overall difference in the PONI – A162G genotype and allele distribution was seen between cases and controls (all p > 0.05). There was, however, a difference in the A allele frequency when the bulbar onset group was compared to the controls (p = 0.03), but this significance disappeared after the Bonferroni correction. Conclusions The results did not show that the – A162G polymorphism of the PON1 gene is a risk factor of sALS in a Polish population; it may affect, however, bulbar onset of the disease.Wstęp i cel pracy Sporadyczna postać stwardnienia bocznego zanikowego (sSLA) jest chorobą zwyrodnieniową układu nerwowego, w której etiopatogenezie kluczową rolę odgrywają interakcje między czynnikami genetycznymi i środowiskowymi. Dotychczasowe badania wskazują na istnienie zależności między polimorfizmami genów PON1 i PON2 a ryzykiem wystąpienia sSLA. Celem pracy było zbadanie, czy istnieje związek między polimorfizmem – A162G miejsca promotorowego genu PON1 a ryzykiem wystąpienia sSLA w populacji polskiej. Materiał i metody Badanie przeprowadzono u 259 chorych, uktórych zgodnie z kryteriami El Escorial rozpoznano pewne lub prawdopodobne SLA (76 osób z postacią opuszkową, 183 osoby z postacią kończynową) oraz u 694 zdrowych ochotników, stanowiących grupę kontrolną dobraną pod względem wieku i płci. Polimorfizm genu PON1 był badany za pomocą reakcji łańcuchowej polimerazy DNA z analizą ilości produktu w czasie rzeczywistym. Wyniki Nie stwierdzono istotnych statystycznie różnic w rozkładzie genotypów i alleli genu PON1 między grupą chorych a grupą kontrolną (p > 0,05). Stwierdzono natomiast różnice w częstości występowania allela A między grupą chorych z postacią opuszkową w porównaniu z grupą kontrolną (p = 0,03), jednak po korekcie Bonferroniego wynik ten nie był już istotny statystycznie. Wnioski Wyniki naszego badania nie wykazały, aby polimorfizm – A162G genu PON1 był czynnikiem ryzyka sSLA w populacji polskiej, jednak sugerują, że może mieć znaczenie dla wystąpienia postaci opuszkowej tej choroby

Preliminary evaluation of central nervous system activity of (E)-N-2-methyl-3-phenylprop-2-enyl ((E)-N- α-methylcinnamyl) derivatives of selected aminoalkanols

A series of (E)-α-methylcinnamyl derivatives of selected aminoalkanols was synthetized and evaluated for activity in central nervous system. All compounds were tested as anticonvulsants and one additionally in antidepressant- and anxiolytic-like assays. The compounds possessed pharmacophoric elements regarded as beneficial for anticonvulsant activity: hydrophobic unit and two hydrogen bonds donor/acceptor features. The compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scPTZ) induced seizures as well as neurotoxicity assessments. Eight of the tested substances showed protection in MES test at the dose of 100 mg/kg. The derivative of 2 aminopropan-1-ol was also tested in 6-Hz test in mice i.p. and showed anticonvulsant activity but at the same time the neurotoxicity was noted. The derivative of 2-amino-1-phenylethanol which possessed additional hydrophobic unit in aminoalkanol moiety was tested in other in vivo assays to evaluate antidepressant- and anxiolytic-like activity. The compound proved beneficial properties especially as anxiolytic agent remaining active in four-plate test in mice at the dose of 2.5 mg/kg (i.p.). In vitro biotransformation studies of 2-amino-1-phenylethanol derivative carried out in mouse liver microsomal assay indicated two main metabolites as a result of aliphatic and aromatic hydroxylation or aliphatic carbonylation. To identify possible mechanism of action, we evaluated serotonin receptors (5-HT1A, 5-HT6 and 5-HT7) binding affinities of the compounds but none of them proved to bind to any of tested receptors

Antidepressant- and anxiolytic-like effects of new dual 5-HT_{1A} and 5-HT_{7} antagonists in animal models

The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14-FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15-FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds

KM-408, a novel phenoxyalkyl derivative as a potential anticonvulsant and analgesic compound for the treatment of neuropathic pain

BACKGROUND: Epilepsy frequently coexists with neuropathic pain. Our approach is based on the search for active compounds with multitarget profiles beneficial in terms of potential side effects and on the implementation of screening for potential multidirectional central activity. METHODS: Compounds were synthesized by means of chemical synthesis. After antiseizure and neurotoxicity screening in vivo, KM-408 and its enantiomers were chosen for analgesic activity evaluations. Further safety studies included acute toxicity in mice, the effect on normal electrocardiogram and on blood pressure in rats, whole body plethysmography in rats, and in vitro and biochemical assays. Pharmacokinetics has been studied in rats after iv and po administration. Metabolism has been studied in vivo in rat serum and urine. Radioligand binding studies were performed as part of the mechanism of action investigation. RESULTS: Selected results for KM-408: K(i) sigma = 7.2*10(–8); K(i) 5-HT(1A) = 8.0*10(–7); ED(50) MES (mice, ip) = 13.3 mg/kg; formalin test (I phase, mice, ip)—active at 30 mg/kg; SNL (rats, ip)—active at 6 mg/kg; STZ-induced pain (mice, ip)—active at 1 mg/kg (von Frey) and 10 mg/kg (hot plate); hot plate test (mice, ip)—active at 30 mg/kg; ED(50) capsaicin test (mice, ip) = 18.99 mg/kg; tail immersion test (mice)—active at 0.5%; corneal anesthesia (guinea pigs)—active at 0.125%; infiltration anesthesia (guinea pigs)—active at 0.125%. CONCLUSIONS: Within the presented study a novel compound, R,S-2-((2-(2-chloro-6-methylphenoxy)ethyl)amino)butan-1-ol hydrochloride (KM-408) with dual antiseizure and analgesic activity has been developed for potential use in neuropathic pain treatment. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-022-00431-7

Chemically homogenous compounds with antagonistic properties at all α1\alpha_{1}-adrenoceptor subtypes but not β1\beta_{1}-adrenoceptor attenuate adrenaline-induced arrhythmia in rats

Studies proved that among all α1-adrenoceptors, cardiac myocytes functionally express only α1A- and α1B-subtype. Scientists indicated that α1A-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α1-adrenoceptors subtypes (i.e. α1A and α1B) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β1- and α1-adrenoceptors blocker with antioxidant properties.To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α1-adrenoceptors subtypes using functional bioassays. We tested antiarrhythmic activity in adrenaline-induced (20 µg/kg i.v.), calcium chloride-induced (140 and 25 mg/kg i.v.) and barium chloride-induced (32 and 10 mg/kg i.v.) arrhythmia models in rats. We also evaluated the influence of studied compounds on blood pressure in rats, as well as lipid peroxidation. All studied compounds showed high affinity towards α1-adrenoceptors but no affinity for β1 receptors. Biofunctional studies revealed that the tested compounds blocked α1A- stronger than α1B-adrenoceptors, but except for HBK-19 they antagonized α1A-adrenoceptor weaker than α1D-subtype. HBK-19 showed the greatest difference in pA2 values - it blocked α1A-adrenoceptors around sevenfold stronger than α1B subtype. All compounds showed prophylactic antiarrhythmic properties in adrenaline-induced arrhythmia, but only the activity of HBK-16, HBK-17, HBK-18 and HBK-19 (ED50=0.18-0.21) was comparable to that of carvedilol (ED50=0.36). All compounds reduced mortality in adrenaline-induced arrhythmia. HBK-16, HBK-17, HBK-18 and HBK-19 showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia. None of the compounds showed activity in calcium chloride- or barium chloride-induced arrhythmias. HBK-16, HBK-17, HBK-18 and HBK-19 decreased heart rhythm at ED84. All compounds significantly lowered blood pressure in normotensive rats. HBK-18 showed the strongest hypotensive properties (the lowest active dose: 0.01 mg/kg). HBK-19 was the only compound in the group, which did not show hypotensive effect at antiarrhythmic doses. HBK-16, HBK-17, HBK-18, HBK-19 showed weak antioxidant properties.Our results indicate that the studied 2-methoxyphenylpiperazine derivatives that possessed stronger α1A-adrenolytic properties (i.e. HBK-16, HBK-17, HBK-18 and HBK-19) were the most compounds in adrenaline-induced arrhythmia. Thus, we suggest that the potent blockade of α1A-receptor subtype is essential to attenuate adrenaline-induced arrhythmia

HBK-17, a 5-HT1A Receptor Ligand With Anxiolytic-Like Activity, Preferentially Activates ß-Arrestin Signaling

Numerous studies have proven that both stimulation and blockade of 5-HT1A and the blockade of 5-HT7 receptors might cause the anxiolytic-like effects. Biased agonists selectively activate specific signaling pathways. Therefore, they might offer novel treatment strategies. In this study, we investigated the anxiolytic-like activity, as well as the possible mechanism of action of 1-[(2,5-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-17). In our previous experiments, HBK-17 showed high affinity for 5-HT1A and 5-HT7 receptors and antidepressant-like properties. We performed the four plate test and the elevated plus maze test to determine anxiolytic-like activity. Toward a better understanding of the pharmacological properties of HBK-17 we used various functional assays to determine its intrinsic activity at 5-HT1A, 5-HT2A, 5-HT7, and D2 receptors and UHPLC-MS/MS method to evaluate its pharmacokinetic profile. We observed the anxiolytic-like activity of HBK-17 in both behavioral tests and the effect was reversed by the pretreatment with WAY-100635, which proves that 5-HT1A receptor activation was essential for the anxiolytic-like effect. Moreover, the compound moderately antagonized D2, weakly 5-HT7 and very weakly 5-HT2A receptors. We demonstrated that HBK-17 preferentially activated ß-arrestin signaling after binding to the 5-HT1A receptor. HBK-17 was rapidly absorbed after intraperitoneal administration and had a half-life of about 150 min. HBK-17 slightly penetrated the peripheral compartment and showed bioavailability of approximately 45%. The unique pharmacological profile of HBK-17 encourages further experiments to understand its mechanism of action fully