Henryk Marona

Ion Channels as Drug Targets in Central Nervous System Disorders

Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na+ channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 – for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Cav1.1-Cav3.3, with even newer nomenclature α1A-α1I and α1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

Evaluation of anticonvulsants for possible use in neuropathic pain.

Neuropathic pain is a kind of pain related with functional abnormality of neurons. Despite large progress in pharmacotherapy, neuropathic pain is still considered an unmet need. Nowadays, there are few drugs registered for this condition, such as pregabalin, gabapentin, duloxetine, carbamazepine, and lidocaine. Among them, pregabalin, gabapentin and carbamazepine are well known antiepileptic drugs. Among the group of new antiepileptic drugs, which are addressed to 1% of human world population suffering from seizures, it turned out that 30% of the seizures resistant to pharmacotherapy has not enough market to justify the costs of drug development. Therefore, it is already a phenomenon that researchers turn their projects toward a larger market, related with possible similar mechanism. Anticonvulsant mechanism of action is in the first place among primary indications for drugs revealing potential analgesic activity. Therefore, many drug candidates for epilepsy, still in preclinical stage, are being evaluated for activity in neuropathic pain. This review is focusing on antiepileptic drugs, which are evaluated for their analgesic activity in major tests related with neuropathic pain. Relation between structure, mechanism of action and result in tests such as the Chung model (spinal nerve ligation SNL), the Bennett model (chronic constriction injury of sciatic nerve CCI) and other tests are considered. The first examples are carbamazepine, gabapentin, and lacosamide as drugs well established in epilepsy market as well as drug candidates such as valnoctamide, and other valproic acid derivatives, novel biphenyl pyrazole derivatives, etc. Moreover, clinical efficacy related with listed animal models has been discussed.

Preliminary evaluation of pharmacological properties of some xanthone derivatives

A series of xanthone derivatives were synthesized and examined for electrocardiographic, antiarrhythmic, hypotensive and anticonvulsant activities as well as for alpha(1)- and beta(1)-adrenergic binding affinities. Among the investigated compounds, some of them exhibited significant antiarrhythmic and/or hypotensive activity. The data obtained via receptor binding assay are in agreement with pharmacological results and could explain antiarrhythmic and/or hypotensive activity of the newly synthesized structures.

Synthesis and Evaluation of Antidepressant‐like Activity of Some 4‐Substituted 1‐(2‐methoxyphenyl)Piperazine Derivatives

A series of new derivatives of N‐(2‐methoxyphenyl)piperazine have been synthesized for their affinity toward serotonergic receptors and for their potential antidepressant‐like activity. They have been evaluated toward receptors 5‐HT1A, 5‐HT6, and 5‐HT7, as well as in vivo in the tail suspension, locomotor activity, and motor co‐ordination tests. All the tested compounds proved very good affinities toward 5‐HT1A and 5‐HT7 receptors. The most promising compound was 1‐[(2‐chloro‐6‐methylphenoxy)ethoxyethyl]‐4‐(2‐methoxyphenyl)piperazine hydrochloride, exhibiting affinity toward receptors Ki <1 nm (5‐HT1A) and Ki = 34 nm (5‐HT7). Antidepressant‐like activity (tail suspension test) was observed at 2.5 mg/kg b.w. (mice, i.p.), and the effect was stronger than that observed for imipramine (5 mg/kg b.w.). Sedative activity was observed at ED50 (locomotor test, mice, i.p.) = 17.5 mg/kg b.w. and neurotoxicity was observed at TD50 (rotarod, mice, i.p.) = 53.2 mg/kg b.w.

Anticonvulsant activity of some xanthone derivatives

A series of appropriate alkanolamine and amide derivatives of xanthone were prepared and evaluated for anticonvulsant activity using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scMet) induced seizures, and for neurotoxicity (TOX) using the rotorod test on mice and rats. The most promising compounds seem to be the appropriate aminoalkanolic derivatives of 6-chloroxanthone, among which the R-(-) and S-(+)-2amino-1-propanol derivatives of 6-chloro-2-methylxanthone (2(a) and 2(b)) displayed anti-MES activity (in mice) with a protective index (TD(50)/ED(50)) of 6.23<6.85, corresponding to that of phenytoin, carbamazepine and valproate. The most active compound, 2(b), was determined to have an affinity to the benzodiazepine (BDZ) receptor and voltage-dependent Ca(2+) channel (VDCC) by using radioligand binding assays. The enantiomeric purities of 2(a) and 2(b) were determined using an analytical liquid chromatography-mass spectrometry method.

Antifungal and Antibacterial Activity of the Newly Synthesized 2-Xanthone Derivatives

A series of 2‐substituted xanthone derivatives 8–20 containing selected allyl, cinnamyl, morpholine, and imidazole moieties were synthesized and tested for their antifungal and antibacterial in‐vitro properties. Of the newly synthesized derivatives, ten revealed antifungal activity especially against Trichophyton mentagrophytes (the biggest inhibition zones ranged 35 mm for 11 and 13). 2‐(3‐(Allylamino)propoxy)‐9H‐xanthen‐9‐one hydrochloride 9 inhibited growth of all of the examined fungal species. Significant efficacy against evaluated yeasts and dermatophytes was also observed for 6‐chloro‐2‐methyl‐9H‐xanthen‐9‐one derivatives 11–13 containing encyclic amine moieties. Additionally, compounds 9, 11, and 12 hindered development of bacteria species but in a lesser degree. They were efficacious against Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis.

Synthesis and evaluation of some xanthone derivatives for anti-arrhythmic, hypotensive properties and their affinity for adrenergic receptors.

A series of 2‐, 4‐ or 2‐methyl‐6‐substituted xanthone derivatives 8–17 containing selected piperazine moieties were synthesized and tested for their electrocardiographic, anti‐arrhythmic, and antihypertensive activity, as well as for the α1‐ and β1‐adrenoceptor binding affinities. Of the newly synthesized derivatives, 2‐(2‐hydroxy‐3‐(4‐(2‐phenoxyethyl)piperazin‐1‐yl)propoxy)‐9H‐xanthen‐9‐one dihydrochloride 9, 4‐(2‐hydroxy‐3‐(4‐(2‐phenoxyethyl)piperazin‐1‐yl)propoxy)‐9H‐xanthen‐9‐one dihydrochloride 12, and 4‐(2‐(4‐(pyridin‐2‐yl)piperazin‐1‐yl)ethoxy)‐9H‐xanthen‐9‐one dihydrochloride 15 possessed significant anti‐arrhythmic activity in the adrenaline‐induced model of arrhythmia, with the ED50 values ranging 1.7–7.2 mg/kg. Compound 15 had the lowest ED50 value equaling 1.7 mg/kg, which was comparable with ED50 value of propranolol, which was used in this test as a reference compound. Compound 9 showed also the strongest hypotensive activity, which persisted for 60 minutes at the dose of 2.5 mg/kg. 2‐(2‐(4‐(2‐Phenoxyethyl)piperazin‐1‐yl)ethoxy)‐9H‐xanthen‐9‐one dihydrochloride 8 also significantly lowered blood pressure at a dose of 2.5 mg/kg but much weaker than compound 9. Binding studies are in agreement with our pharmacological results and could explain anti‐arrhythmic effect of compound 15 and anti‐arrhythmic and hypotensive effects of compounds 9 and 12.

Evaluation of mutagenic and antimutagenic properties of some bioactive xanthone derivatives using Vibrio harveyi test

Aims:  Drug safety evaluation plays an important role in the early phase of drug development, especially in the preclinical identification of compounds’ biological activity. The Vibrio harveyi assay was used to assess mutagenic and antimutagenic activity of some aminoalkanolic derivatives of xanthone (1–5), which were synthesized and evaluated for their anticonvulsant and hemodynamic activities.

Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT1A and 5-HT7 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.

Synthesis and evaluation of pharmacological properties of some new xanthone derivatives with piperazine moiety

A series of new xanthone derivatives with piperazine moiety [1-7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α₁ and β₁ adrenergic as well as 5-HT₁A, 5-HT₆ and 5-HT₇b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT₁A receptors (Ki=24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED₅₀ determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration.