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

Synthesis and evaluation of anticonvulsant activity of N-(2,5-dimethylphenoxy)- and N-[(2,3,5-trimethylphenoxy)alkyl]aminoalkanols

A series of new N-(2,5-dimethylphenoxy)- and N-(2,3,5-trimethylphenoxy)alkylaminoalkanols [I-XVII] was synthesized and evaluated for anticonvulsant activity. Pharmacological tests included maximal electroshock (MES) and subcutaneous pentetrazole seizure threshold (scMet) assays as well as neurotoxicity (TOX) evaluation in mice after intraperitoneal (i.p.) administration and/or in rats after oral (p.o.) administration. The most active compound was R-2N-[(2,3,5-trimethylphenoxy)ethyl]aminobutan-1-ol, which exhibited 100% activity in MES at the dose of 30 mg/kg body weight (mice, i.p.) and 75% activity in MES at 30 mg/kg b.w. (rats, p.o.) without neurotoxicity at the active doses

Skin metabolism established with the use of MetaSite for selected retinoids employed in topical and systemic treatment of various skin disorders and found in cosmeceuticals

Purpose. Besides being widely used in cosmetics, retinoids are potent therapeutic agents used topically and systemically as anti-acne agents. The aim of this study was to predict with the use of MetaSite the skin metabolism of selected retinoids employed in treatment of skin disorders and found in cosmeceuticals. The following compounds were studied: retinol, retinaldehyde, retinoic acid, retinyl acetate, retinyl palmitate, acitretin, etretinate, adapalene and bexarotene. Methods. MetaSite, Molecular Discovery Ltd. is a computational model that enables prediction of cytochrome P450-dependant metabolism. This software indicates atoms in the molecule structure that are mostly vulnerable to metabolic changes and predicts the metabolite structures. Results. MetaSite indicated that retinol and retinal metabolites were obtained through hydroxylation of the methyl group located in the position 3 of the aliphatic chain, whereas retinoic acid biotransformation would occur principally in the carbon atom situated in the position 4 in the cyclohexene ring. In acitretin molecule, carbon atom of the methoxy group attached to the benzene ring displayed the highest probability of biotransformation. In etretinate, metabolic reactions would occur principally on the carbon atom of the final ethyl group of the molecule. Conclusions. MetaSite metabolism predictions for retinoic acid, acitretin, etretinate, adapalene and bexarotene were in agreement with experimental findings. In case of compounds being converted by catalysts other than cytochrome P450 enzymes, the primary metabolites predicted by MetaSite differ from those reported previously. In conclusion, MetaSite is a useful tool that can aid identification of the major metabolites of compounds being administered topically

HBK-14 and HBK-15 with antidepressant-like and/or memory-enhancing properties increase serotonin levels in the hippocampus after chronic treatment in mice

5-HT(1A) and 5-HT(7) receptor ligands might have antidepressant-like properties and improve cognitive function. We previously reported significant antidepressant- and anxiolytic-like effects of two dual 5-HT(1A) and 5-HT(7) receptor antagonists in various behavioral tests in rodents. As a continuation of our previous experiments, in this study we aimed to investigate whether chronic administration of 1-[(2,6-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15) caused antidepressant-like effects and elevated serotonin levels in the murine hippocampus. We also evaluated cholinolytic properties and the influence of acute administration of both compounds on cognitive function in mice. To assess antidepressant-like properties and the influence on learning and memory we used forced swim test and step-through passive avoidance task in mice, respectively. Both compounds showed antidepressant-like properties and significantly elevated serotonin levels in the hippocampus after chronic treatment (HBK-14 – 2.5 mg/kg; HBK-15 – 0.625 and 1.25 mg/kg). HBK-15 administered chronically antidepressant-like activity at lower dose (0.625 mg/kg) than the dose active after acute treatment (1.25 mg/kg). None of the compounds affected locomotor activity of mice. HBK-15 possessed very weak cholinolytic properties, whereas HBK-14 did not show any effect on muscarinic receptors. Only HBK-15 (0.625 mg/kg) presented memory-enhancing properties and ameliorated cognitive impairments caused by scopolamine (1 mg/kg). Our results indicate that 5-HT(1A) and 5-HT(7) antagonists might have potential in the treatment of depression and possess positive influence on cognitive function

HBK-14 and HBK-15 do not influence blood pressure, lipid profile, glucose level, or liver enzymes activity after chronic treatment in rats

Older and even new antidepressants cause adverse effects, such as orthostatic hypotension, hyper- or hypoglycemia, liver injury or lipid disorders. In our previous experiments we showed significant antidepressant- and anxiolytic-like activities of dual 5-HT1A and 5-HT7 antagonists with α1-adrenolitic properties i.e. 1-[(2,6-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15). Here, we evaluated the influence of chronic administration of HBK-14 and HBK-15 on blood pressure (non-invasive blood pressure measurement system for rodents), lipid profile (total cholesterol, low density lipoproteins-LDL, high density lipoproteins-HDL, triglycerides), glucose level, and liver enzymes activity (aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase). We determined potential antihistaminic (isolated guinea pig ileum) and antioxidant properties (ferric reducing ability of plasma-FRAP, non-protein thiols-NPSH, stable free radical diphenylpicrylhydrazyl-DPPH) cytotoxicity. Our experiments revealed that HBK-14 and HBK-15 did not influence blood pressure, lipid profile, glucose level or liver enzymes activity in rats after 2-week treatment. We also showed that none of the compounds possessed antioxidant or cytotoxic properties at antidepressant- and anxiolytic-like doses. HBK-14 and HBK-15 very weakly blocked H1 receptors in guinea pig ileum. Positive results of our preliminary experiments on the safety of HBK-14 and HBK-15 encourage further studies concerning their effectiveness in the treatment of depression and/or anxiety disorders