RESUMO
The platelet aggregation inhibitory activity of selected xanthine-based adenosine A2A and A2B receptor antagonists was investigated, and attempts were made to explain the observed effects. The selective A2B receptor antagonist PSB-603 and the A2A receptor antagonist TB-42 inhibited platelet aggregation induced by collagen or ADP. In addition to adenosine receptor blockade, the compounds were found to act as moderately potent non-selective inhibitors of phosphodiesterases (PDEs). TB-42 showed the highest inhibitory activity against PDE3A along with moderate activity against PDE2A and PDE5A. The antiplatelet activity of PSB-603 and TB-42 may be due to inhibition of PDEs, which induces an increase in cAMP and/or cGMP concentrations in platelets. The xanthine-based adenosine receptor antagonists were found to be non-cytotoxic for platelets. Some of the compounds showed anti-oxidative properties reducing lipid peroxidation. These results may provide a basis for the future development of multi-target xanthine derivatives for the treatment of inflammation and atherosclerosis and the prevention of heart infarction and stroke.
Assuntos
Aterosclerose , Plaquetas , Animais , Ratos , Xantina/farmacologia , AdenosinaRESUMO
Pain is a very unpleasant experience that makes life extremely uncomfortable. The histamine H4 receptor (H4R) is a promising target for the treatment of inflammatory and immune diseases, as well as pain. H4R ligands have demonstrated analgesic effects in a variety of pain models, including inflammatory pain. Continuing the search for active H4R ligands among the alkyl derivatives of 1,3,5-triazine, we obtained 19 new compounds in two series: acyclic (I) and aliphatic (II). In vitro pharmacological evaluation showed their variable affinity for H4R. The majority of compounds showed a moderate affinity for this receptor (Ki > 100 nM), while all compounds tested in ß-arrestin and cAMP assays showed antagonistic activity. The most promising, compound 6, (4-(cyclopentylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine; Ki = 63 nM) was selected for further in vitro evaluation: blood-brain barrier permeability (PAMPA assay; Pe = 12.26 × 10-6 cm/s) and toxicity tests (HepG2 and SH-5YSY cells; no toxicity up to 50 µM). Next, compound 6 tested in vivo in a carrageenan-induced inflammatory pain model showed anti-inflammatory and analgesic effects (strongest at 50 mg/kg i.p.). Furthermore, in a histamine- and chloroquine-induced pruritus model, compound 6 at a dose of 25 mg/kg i.p. and 50 mg/kg i.p., respectively, reduced the number of scratch bouts. Thus, compound 6 is a promising ligand for further studies.
Assuntos
Histamina , Triazinas , Humanos , Receptores Histamínicos H4 , Triazinas/farmacologia , Triazinas/uso terapêutico , Receptores Histamínicos , Dor/tratamento farmacológico , Ligantes , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Receptores Acoplados a Proteínas GRESUMO
The multitarget-directed ligands demonstrating affinity to histamine H3 receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective treatment of Alzheimer's disease. In this study, a novel series of benzophenone derivatives was designed and synthesized. Among these derivatives, we identified compound 6 with a high affinity for H3R (Ki = 8 nM) and significant inhibitory activity toward BuChE (IC50 = 172 nM and 1.16 µM for eqBuChE and hBuChE, respectively). Further in vitro studies revealed that compound 6 (4-fluorophenyl) (4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)methanone) displays moderate metabolic stability in mouse liver microsomes, good permeability with a permeability coefficient value (Pe) of 6.3 × 10-6 cm/s, and its safety was confirmed in terms of hepatotoxicity in the HepG2 cell line. Therefore, we investigated the in vivo activity of compound 6 in the Passive Avoidance Test and the Formalin Test. While compound 6 did not show a statistically significant influence on memory and learning, it showed analgesic properties in both acute (ED50 = 20.9 mg/kg) and inflammatory (ED50 = 17.5 mg/kg) pain.
Assuntos
Doença de Alzheimer , Receptores Histamínicos H3 , Camundongos , Animais , Colinesterases/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Histamina , Receptores Histamínicos H3/metabolismo , Inibidores da Colinesterase/farmacologia , Receptores Histamínicos , Ligantes , Relação Estrutura-AtividadeRESUMO
Alzheimer's disease (AD) is a complex and incurable illness that requires the urgent approval of new effective drugs. However, since 2003, no new molecules have shown successful results in clinical trials, thereby making the common "one compound - one target" paradigm questionable. Recently, the multitarget-directed ligand (MTDL) approach has gained popularity, as compounds targeting at least two biological targets may be potentially more effective in treating AD. On the basis of these findings, we designed, synthesized, and evaluated through biological assays a series of derivatives of alicyclic amines linked by an alkoxy bridge to an aromatic lipophilic moiety of [1,1'-biphenyl]-4-carbonitrile. The research results revealed promising biological activity of the obtained compounds toward the chosen targets involved in AD pathophysiology; the compounds showed high affinity (mostly low nanomolar range of Ki values) for human histamine H3 receptors (hH3R) and good nonselective inhibitory potency (micromolar range of IC50 values) against acetylcholinesterase from electric eel (eeAChE) and equine serum butyrylcholinesterase (eqBuChE). Moreover, micromolar/submicromolar potency against human monoamine oxidase B (hMAO B) was detected for some compounds. The study identified compound 5 as a multiple hH3R/eeAChE/eqBuChE/hMAO B ligand (5: hH3R Ki = 9.2 nM; eeAChE IC50 = 2.63 µM; eqBuChE IC50 = 1.30 µM; hMAO B IC50 = 0.60 µM). Further in vitro studies revealed that compound 5 exhibits a mixed type of eeAChE and eqBuChE inhibition, good metabolic stability, and moderate hepatotoxicity effect on HepG2 cells. Finally, compound 5 showed a beneficial effect on scopolamine-induced memory impairments, as assessed by the passive avoidance test, thus revealing the potential of this compound as a promising agent for further optimization for AD treatment.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Compostos de Bifenilo/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Receptores Histamínicos H3/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Humanos , Ligantes , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Relação Estrutura-AtividadeRESUMO
We report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (MES) test, the pentylenetetrazole-induced seizure model (scPTZ), and the psychomotor 6 Hz (32 mA) seizure model in mice. Compound 14 showed the most robust anticonvulsant activity (ED50 MES = 49.6 mg/kg, ED50 6 Hz (32 mA) = 31.3 mg/kg, ED50scPTZ = 67.4 mg/kg). Notably, it was also effective in the 6 Hz (44 mA) model of drug-resistant epilepsy (ED50 = 63.2 mg/kg). Apart from favorable anticonvulsant properties, compound 14 revealed a high efficacy against pain responses in the formalin-induced tonic pain, the capsaicin-induced neurogenic pain, as well as in the oxaliplatin-induced neuropathic pain in mice. Moreover, compound 14 showed distinct anti-inflammatory activity in the model of carrageenan-induced aseptic inflammation. The mechanism of action of compound 14 is likely complex and may result from the inhibition of peripheral and central sodium and calcium currents, as well as the TRPV1 receptor antagonism as observed in the in vitro studies. This lead compound also revealed beneficial in vitro ADME-Tox properties and an in vivo pharmacokinetic profile, making it a potential candidate for future preclinical development. Interestingly, the in vitro studies also showed a favorable induction effect of compound 14 on the viability of neuroblastoma SH-SY5Y cells.
Assuntos
Acetamidas/administração & dosagem , Analgésicos/administração & dosagem , Anticonvulsivantes/administração & dosagem , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Dor/tratamento farmacológico , Convulsões/tratamento farmacológico , Acetamidas/farmacologia , Administração Intravenosa , Analgésicos/química , Analgésicos/farmacologia , Animais , Anticonvulsivantes/farmacologia , Canais de Cálcio/metabolismo , Capsaicina/efeitos adversos , Modelos Animais de Doenças , Epilepsia Resistente a Medicamentos/etiologia , Epilepsia Resistente a Medicamentos/metabolismo , Eletrochoque/efeitos adversos , Formaldeído/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Oxaliplatina/efeitos adversos , Dor/induzido quimicamente , Dor/metabolismo , Pentilenotetrazol/efeitos adversos , Convulsões/etiologia , Convulsões/metabolismo , Canais de Sódio/metabolismo , Canais de Cátion TRPV/metabolismoRESUMO
Neurodegenerative diseases, e.g., Alzheimer's disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H3 receptors (H3Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H3R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H3R ligands. Most of these compounds show high affinity for human H3R (Ki < 150 nM) and submicromolar inhibition of BuChE (IC50 < 1 µM). Among all the tested compounds, 19 (E153, 1-(5-([1,1'-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H3R, with a Ki value of 33.9 nM, and for equine serum BuChE, with an IC50 of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC50 of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents.
Assuntos
Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Aminas/química , Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Monoaminoxidase/química , Receptores Histamínicos H3/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Butirilcolinesterase/metabolismo , Linhagem Celular , Inibidores da Colinesterase/síntese química , Humanos , Ligantes , Masculino , Camundongos , Modelos Animais , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/metabolismo , Receptores Histamínicos H3/química , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: The main objective of the present work was to assess the utility of KA-104 as potential therapy for drug-resistant seizures and neuropathic pain, and to characterize its druglike properties in a series of absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) studies. We also aimed to establish its mechanism of action in electrophysiological studies. METHODS: The activity of KA-104 against drug-resistant seizures was tested in the mouse 6-Hz (44-mA) model, whereas the antinociceptive activity was assessed with the capsaicin- and oxaliplatin-induced pain models in mice. The patch-clamp technique was used to study the influence of KA-104 on fast voltage-gated sodium currents in rat prefrontal cortex pyramidal neurons. The pharmacokinetic profile was determined after intraperitoneal (ip) injection in mice. The in vitro ADME-Tox properties were studied by applying routine testing procedures. RESULTS: KA-104 was effective in the 6-Hz (44-mA) model (median effective dose [ED50 ] = 73.2 mg/kg) and revealed high efficacy in capsaicin-induced neurogenic pain as well as in oxaliplatin-induced neuropathic pain in mice. Patch-clamp technique showed that KA-104 reversibly inhibits voltage-gated sodium currents. KA-104 was rapidly absorbed after the ip injection and showed relatively good penetration through the blood-brain barrier. This molecule was also characterized by high passive permeability, moderate influence on CYP2C9, and negligible hepatotoxicity on HepG2 cells. SIGNIFICANCE: The results reported herein indicate that KA-104 is a new wide-spectrum multitargeted anticonvulsant with favorable in vitro ADME-Tox properties. Importantly, this compound may also prove to become an interesting and hopefully more effective therapeutic option for treatment of neuropathic pain.
Assuntos
Analgésicos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Neuralgia/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Células Hep G2 , Humanos , Masculino , Camundongos , Neuralgia/patologia , Medição da Dor/métodosRESUMO
Epilepsy belongs to the most common and debilitating neurological disorders with multifactorial pathophysiology and a high level of drug resistance. Therefore, with the aim of searching for new, more effective, and/or safer therapeutics, we discovered a focused series of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant properties. We applied an optimized coupling reaction yielding several hybrid compounds that showed broad-spectrum activity in widely accepted animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure model in mice. The most potent anticonvulsant activity and favorable safety profile was demonstrated for compound 30 (median effective dose (ED50) MES = 45.6 mg/kg, ED50 6 Hz (32 mA) = 39.5 mg/kg, median toxic dose (TD50) (rotarod test) = 162.4 mg/kg). Anticonvulsant drugs often show activity in pain models, and compound 30 was also proven effective in the formalin test of tonic pain, the capsaicin-induced pain model, and the oxaliplatin (OXPT)-induced neuropathic pain model in mice. Our studies showed that the most plausible mechanism of action of 30 involves inhibition of calcium currents mediated by Cav1.2 (L-type) channels. Importantly, 30 revealed high metabolic stability on human liver microsomes, negligible hepatotoxicity, and relatively weak inhibition of CYP3A4, CYP2D6, and CYP2C9 isoforms of cytochrome P450, compared to reference compounds. The promising in vivo activity profile and drug-like properties of compound 30 make it an interesting candidate for further preclinical development.
Assuntos
Acetamidas/farmacologia , Analgésicos/farmacologia , Anticonvulsivantes/farmacologia , Epilepsia Parcial Complexa/tratamento farmacológico , Dor/tratamento farmacológico , Pirrolidinas/farmacologia , Convulsões/tratamento farmacológico , Acetamidas/síntese química , Analgésicos/síntese química , Animais , Anticonvulsivantes/síntese química , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Capsaicina , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Eletrochoque/métodos , Epilepsia Parcial Complexa/induzido quimicamente , Epilepsia Parcial Complexa/genética , Epilepsia Parcial Complexa/fisiopatologia , Formaldeído , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Oxaliplatina , Dor/induzido quimicamente , Dor/genética , Dor/fisiopatologia , Pirrolidinas/síntese química , Teste de Desempenho do Rota-Rod , Convulsões/induzido quimicamente , Convulsões/genética , Convulsões/fisiopatologia , Relação Estrutura-AtividadeRESUMO
The subject of the work was the synthesis of new derivatives of1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione with potential analgesic and sedative activity. Eight compounds werereceived. The analgesic activity of the new compounds was confirmed in the "hot plate" test and in the "writhing" test. All tested imides 8-15 were more active in the "writhing" test than aspirin, and two of them, 9 and 11, were similar to morphine. In addition, all of the new imides inhibited the locomotor activity in mice to a statistically significant extent, and two of them also prolonged the duration of thiopental sleep.On the basis of the results obtained for the previously synthesized imides and the results presented in this paper, an attempt was madeto determine the relationship between thechemical structure of imides and their analgesic and sedativeproperties.
Assuntos
Analgésicos/farmacologia , Hipnóticos e Sedativos/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Analgésicos/química , Animais , Hipnóticos e Sedativos/química , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Piridinas/química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
Gastrotoxicity continues to be a major issue in therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). Medicine is yet to develop absolutely safe analgesics. Numerous strategies are employed to discover new, safer NSAIDs, for example selective inhibition of cyclooxygenase-2, new molecular targets (e.g. microsomal prostaglandin E2 synthase-1), incorporation of cytoprotective compounds in the drug molecule or modification of the classic NSAIDs currently available on the market. The research presented in this paper is indicative of a current worldwide trend in this area of science, and is an example of the fourth strategy noted above. Two series of new arylpiperazine derivatives of the classic NSAID - piroxicam, were developed by conventional synthesis. The full range of compounds obtained proved to be between two and five times analgesically more potent than the reference drug and, most importantly, they did not show any ulcerogenic activity.
Assuntos
Analgésicos/química , Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Analgésicos/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Masculino , Camundongos , Modelos Moleculares , Piperazinas/efeitos adversos , Piroxicam/efeitos adversos , Piroxicam/análogos & derivados , Piroxicam/farmacologia , Ratos Wistar , Úlcera/induzido quimicamenteRESUMO
This study focuses on the design, synthesis, molecular modeling and biological evaluation of a novel group of alkyl-1,3,5-triazinyl-methylpiperazines. New compounds were synthesized and their affinities for human histamine H4 receptor (hH4R) were evaluated. Among them, 4-(cyclohexylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (14) exhibited hH4R affinity with a Ki of 160â¯nM and behaved as antagonist in functional assays: the cellular aequorin-based assay (IC50â¯=â¯32â¯nM) and [35S]GTPγS binding assay (pKbâ¯=â¯6.67). In addition, antinociceptive activity of 14in vivo was observed in Formalin test (in mice) and in Carrageenan-induced acute inflammation test (in rats).
Assuntos
Analgésicos/farmacologia , Inflamação/tratamento farmacológico , Receptores Histamínicos H4/antagonistas & inibidores , Triazinas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Carragenina , Relação Dose-Resposta a Droga , Formaldeído , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Ligantes , Camundongos , Estrutura Molecular , Ratos , Receptores Histamínicos H4/metabolismo , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/químicaRESUMO
BACKGROUND AND AIMS: Metabolic syndrome associated with insulin resistance and hypertension is often caused by excessive fructose consumption. Treatment of hypertension in patients with metabolic syndrome is a difficult task as many antihypertensive drugs have adverse effects on the metabolic profile. We investigated if MH-76 and MH-79, non-quinazoline α1-adrenoceptor antagonists with an additional ability to stimulate NO/cGMP/K+ pathway, ameliorates metabolic syndrome in fructose-fed rats. As reference compound prazosin was used. METHODS AND RESULTS: Male rats were divided into 5 groups (n = 8) and studied for 18 weeks: group control: standard diet and drinking water; group Fructose: high-fructose diet (20% fructose in drinking water); groups Fructose + MH-76, Fructose + MH-79, Fructose + prazosin: high-fructose diet with subsequent MH-76, MH-79 (5 mg/kg/day ip) or prazosin (0.2 mg/kg/day ip) treatment 12 weeks later. In addition to their antihypertensive effect, the studied compounds reversed endothelial dysfunction, decreased hyperglycemia and hypertriglyceridemia, as well as prevented abdominal adiposity. Moreover, MH-76 reduced insulin resistance and decreased TNF-α concentration and lipid peroxidation in adipose tissue. Prazosin treatment exerted an antihypertensive effect, reduced hyperglycemia but did not improve endothelial dysfunction, insulin resistance, and abdominal adiposity. The lower efficacy of prazosin may be the result of its short half-time and the lack of described pleiotropic effects. CONCLUSIONS: α1-adrenoceptor blockade, endothelial protection, TNF-α suppressing and antioxidant activity together with favorable pharmacokinetic parameters determines high efficacy of MH-76, leading to the effective improvement of hemodynamic and metabolic disturbances in metabolic syndrome. The use of non-quinazoline, multiple-targeted α1-blockers may be an interesting option for treatment of hypertension with metabolic complications.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Frutose , Hipertensão/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , Piperazinas/farmacologia , Prazosina/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/farmacocinética , Animais , Anti-Hipertensivos/farmacocinética , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/etiologia , Piperazinas/farmacocinética , Ratos Wistar , Fator de Necrose Tumoral alfa/sangueRESUMO
A series of 1- and 2-naphthyloxy derivatives were synthesized and evaluated for histamine H3 receptor affinity. Most compounds showed high affinities with Ki values below 100â¯nM. The most potent ligand, 1-(5-(naphthalen-1-yloxy)pentyl)azepane (11) displayed high affinity for the histamine H3 receptor with a Ki value of 21.9â¯nM. The antagonist behaviour of 11 was confirmed both in vitro in the cAMP assay (IC50â¯=â¯312â¯nM) and in vivo in the rat dipsogenia model (ED50â¯=â¯3.68â¯nM). Moreover, compound 11 showed positive effects on scopolamine induced-memory deficits in mice (at doses of 10 and 15â¯mg/kg) and an analgesic effect in the formalin test in mice with ED50â¯=â¯30.6â¯mg/kg (early phase) and ED50â¯=â¯20.8â¯mg/kg (late phase). Another interesting compound, 1-(5-(Naphthalen-1-yloxy)pentyl)piperidine (13; H3R Kiâ¯=â¯53.9â¯nM), was accepted for Anticonvulsant Screening Program at the National Institute of Neurological Disorders and Stroke/National Institute of Health (Rockville, USA). The screening was performed in the maximal electroshock seizure (MES), the subcutaneous pentylenetetrazole (scPTZ) and the 6-Hz psychomotor animal models of epilepsy. Neurologic deficit was evaluated by the rotarod test. Compound 13 inhibited convulsions induced by the MES with ED50 of 19.2â¯mg/kg (mice, i.p.), 17.8 (rats, i.p.), and 78.1 (rats, p.o.). Moreover, 13 displayed protection against the 6-Hz psychomotor seizures (32â¯mA) in mice (i.p.) with ED50 of 33.1â¯mg/kg and (44â¯mA) ED50 of 57.2â¯mg/kg. Furthermore, compounds 11 and 13 showed in vitro weak influence on viability of tested cell lines (normal HEK293, neuroblastoma IMR-32, hepatoma HEPG2), weak inhibition of CYP3A4 activity, and no mutagenicity. Thus, these compounds may be used as leads in a further search for histamine H3 receptor ligands with promising in vitro and in vivo activity.
Assuntos
Anticonvulsivantes/farmacologia , Azepinas/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Naftalenos/farmacologia , Piperidinas/farmacologia , Analgésicos/administração & dosagem , Analgésicos/síntese química , Analgésicos/farmacologia , Analgésicos/toxicidade , Animais , Antazolina/farmacologia , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/síntese química , Anticonvulsivantes/toxicidade , Atropina/farmacologia , Azepinas/administração & dosagem , Azepinas/síntese química , Azepinas/toxicidade , Relação Dose-Resposta a Droga , Cobaias , Células HEK293 , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/toxicidade , Humanos , Ligantes , Masculino , Camundongos , Naftalenos/administração & dosagem , Naftalenos/síntese química , Naftalenos/toxicidade , Piperidinas/administração & dosagem , Piperidinas/síntese química , Piperidinas/toxicidade , Ratos Wistar , Receptor Muscarínico M3/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H3/metabolismoRESUMO
As a continuation of our search for novel histamine H3 receptor ligands, a series of new acetyl and propionyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer, composed of six various 4N-substituted piperazine moieties were evaluated for their binding properties at human histamine H3 receptors (hH3R). In vitro test results proved the 4-pyridylpiperazine moiety as crucial element for high hH3R affinity (hH3R Kiâ¯=â¯5.2-115â¯nM). Moreover introduction of carbonyl group containing residues in the lipophilic part of molecules instead of branched alkyl substituents resulted in increased affinity in correlation to previously described series, whereas propionyl derivatives showed slightly higher affinities than those of acetyl (16 and 22vs.4 and 10; hH3R Kiâ¯=â¯5.2 and 15.4â¯nM vs. 10.2 and 115â¯nM, respectively). These findings were confirmed by molecular modelling studies, demonstrating multiple ligand-receptor interactions. Furthermore, pharmacological in vivo test results of compound 4 clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound. Likewise, its protective action against hyperglycemia and the development of overweight has been shown. In order to estimate drug-likeness of compound 4, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed.
Assuntos
Antineoplásicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Piperazina/farmacologia , Receptores Histamínicos H3/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/química , Humanos , Ligantes , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Piperazina/síntese química , Piperazina/química , Ratos , Relação Estrutura-AtividadeRESUMO
OBJECTIVE AND DESIGN: Histamine H4 receptor (H4R) offers a great potential for new therapeutic strategies for the treatment of inflammation-based diseases. The aim of this study is to present the pharmacological profile of two recently synthesized ligands of H4R with particular reference to their anti-inflammatory and analgesic activity. MATERIALS AND SUBJECTS: We used mice and rats in the in vivo tests. We also used murine RAW 264.7 cells and isolated guinea-pig ileum in in vitro test. TREATMENTS: In the in vivo tests, animals were pre-treated with the increasing doses of investigated compounds (12.5, 25 and 50 mg/kg) and reference compounds: JNJ7777120 (25 mg/kg), indomethacin (10 mg/kg). Macrophages were pre-treated with two concentrations of tested compounds 100 and 10 µM. METHODS: We examined anti-inflammatory and analgesic effects of the new H4R antagonists in the in vivo models of inflammation induced by carrageenan or zymosan. We assessed the level of cAMP and release of cytokines, ROS and NO in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Moreover, we assessed the affinity of the investigated compounds for histamine H1 receptor in functional studies. RESULTS: Both investigated compounds reduced paw edema, mechanical and thermal hyperalgesia in the carrageenan-induced acute inflammation. Moreover, administration of the investigated compounds resulted in decreased granulocyte influx and attenuated nociceptive reaction in the zymosan-induced peritonitis model. In the same model of inflammation, the investigated compounds reduced vascular permeability; however, this effect was observed only after the highest applied dose. Furthermore, the test compounds had no impact on cell viability in the experiments on RAW 264.7 macrophages. In these cells, stimulated with LPS, the test compounds decreased reactive oxygen species (ROS) production. They increased the cellular concentration of cAMP and attenuated the production of inflammatory cytokines such as TNFα and IL-1ß. All results were comparable to those obtained for the reference compound JNJ7777120 with the exception of the impact on NO production. Nevertheless, this effect was similar to that obtained for the other reference compound rolipram, which is a phosphodiesterase 4 (PDE 4) inhibitor. Further experiments revealed that both of the investigated compounds possessed relatively low affinity for histamine H1 receptor and do not inhibit the activity of the PDE 4B1 enzyme. In addition, all the effects of the investigated compounds in in vivo experiments were observed at doses that did not cause neurologic deficits in rotarod test and did not reduce spontaneous locomotor activity. CONCLUSIONS: Our results demonstrate the anti-inflammatory and analgesic activity of the new aryl-1,3,5-triazine derivatives, which are primarily H4R-dependent.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antagonistas dos Receptores Histamínicos/uso terapêutico , Triazinas/uso terapêutico , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Carragenina , AMP Cíclico/metabolismo , Cobaias , Antagonistas dos Receptores Histamínicos/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Ligantes , Lipopolissacarídeos , Masculino , Camundongos , Óxido Nítrico/metabolismo , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/metabolismo , Células RAW 264.7 , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores Histamínicos/metabolismo , Triazinas/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , ZimosanRESUMO
Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H3 receptor. Two series of compounds were obtained with a meta- and a para-biphenyl moiety. The alkyl chain spacer contained five and six carbon atoms. The highest affinity among all compounds was shown by 1-(6-(3-phenylphenoxy)hexyl)azepane (13) with a Ki value of 18nM. Two para-biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine (14; Ki=25nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane (16; Ki=34nM), classified as antagonists in a cAMP accumulation assay (IC50=4 and 9nM, respectively), were studied in detail. Compounds 14 and 16 blocked RAMH-induced dipsogenia in rats (ED50 of 2.72mg/kg and 1.75mg/kg respectively), and showed high selectivity (hH4R vs hH3R>600-fold) and low toxicity (hERG inhibition: IC50>1.70µM; hepatotoxicity IC50>12.5µM; non-mutagenic up to 10µM). Furthermore, the metabolic stability was evaluated in vitro on human liver microsomes (HLMs) and/or rat liver microsomes (RLMs). Metabolites produced were analyzed and tentatively identified by UPLC-MS techniques. The results demonstrated easy hydroxylation of the biphenyl ring.
Assuntos
Azepinas/farmacologia , Piperidinas/farmacologia , Receptores Histamínicos H3/metabolismo , Animais , Azepinas/síntese química , Azepinas/química , Proliferação de Células , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cobaias , Células HEK293 , Células Hep G2 , Humanos , Ligantes , Masculino , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Ratos , Ratos Wistar , Receptor Muscarínico M3/antagonistas & inibidores , Receptor Muscarínico M3/metabolismo , Receptores Histamínicos H1/metabolismo , Relação Estrutura-AtividadeRESUMO
In the search for new hypotensive agents some new aroxyalkyl or aroxyethoxyethyl derivatives of piperazine have been synthesized and evaluated for their pharmacological properties. Pharmacological tests included receptor binding assays toward adrenergic receptors α1, α2 and ß1, additionally 5-HT1A, functional bioassay and in vivo evaluation of hypotensive activity as well as antidepressant-like potential. All the tested compounds exhibited α1-antagonistic properties, three of them possessed also hypotensive activity in rats. The most promising compound 3 1-[4-(2,6-dimethylphenoxy)butyl]-4-(2-methoxyphenyl)piperazine hydrochloride was a selective α1 receptor antagonist (Ki=23.5±1.3, α1/α2=15.77, pKB=8.538±0.109). It was active in all tested doses in vivo (1, 0.5, and 0.1mg/kg) and it reduced blood pressure by 10-13% at the dose of 1mg/kg (rats, i.v.). Compound 5 1-[2-(2,3-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine dihydrochloride exhibited the lowest dose for antidepressant-like activity 5mg/kgb.w. (mice, i.p.) without influence on spontaneous activity (mice, i.p.).
Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/farmacologia , Animais , Antidepressivos de Segunda Geração/síntese química , Antidepressivos de Segunda Geração/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacologia , Linhagem Celular Tumoral , Humanos , Camundongos , RatosRESUMO
A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their relaxant effects in the rat aorta. Evaluation of prepared derivatives demonstrated that compound (8a) is probably a non-selective phosphodiesterase (PDE) inhibitor, as it induced aortic relaxation through endothelium-independent mechanism.
Assuntos
Aorta/efeitos dos fármacos , Aorta/fisiologia , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/análogos & derivados , Vasodilatação/efeitos dos fármacos , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Inibidores da Fosfodiesterase 5/síntese química , Inibidores da Fosfodiesterase 5/química , Ratos , Ratos Wistar , Citrato de Sildenafila/química , Citrato de Sildenafila/farmacologia , Relação Estrutura-AtividadeRESUMO
The compound MH-78 ((+/-)-1-(2,6-dimethylphenoxy)-3-{4-[2-(2-methoxyphenoxy)ethyl]-piperazin-1-yl}propan-2-ol dihydrochloride) contains structural elements that are typical for α1- and ß-blockers. This study aimed to investigate the hypotensive activity as well as the in vitro and in vivo cardiovascular effects of a novel α1- and ß-adrenoceptor antagonist (MH-78) and compare it with carvedilol and urapidil. The procedures were performed on aortic rings of normotensive anesthetized rats. MH-78 decreased the blood pressure and heart rate after intravenous and oral administration. MH-78 possesses both α1- and ß-adrenoceptor blocking activity, which was confirmed in the in vivo study. In biofunctional assays, MH-78 displayed vasorelaxant activity due to α1-adrenoceptor antagonism and calcium channel blocking properties. Moreover, in endothelium-intact aortic rings, pretreatment with Nω-nitro-L-arginine methyl ester (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the MH-78-induced vasorelaxation to a level that is characteristic for MH-78 affinity to α1-adrenoceptors. Our results demonstrated that MH-78 possesses α1- and ß-adrenoceptor blocking properties and induces potent hypotensive and vasorelaxant effects. Moreover, it relaxes vascular smooth muscle not only due to α1-adrenoceptor blocking activity, but also via the endothelium-dependent nitric oxide/soluble guanylyl cyclase/cyclic guanosine monophosphate signalling pathway.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Anti-Hipertensivos/farmacologia , Éteres Fenílicos/farmacologia , Piperazinas/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiologia , GMP Cíclico/metabolismo , Epinefrina/farmacologia , Guanilato Ciclase/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/fisiologia , Técnicas In Vitro , Masculino , Metoxamina/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Óxido Nítrico/metabolismo , Norepinefrina/farmacologia , Cloreto de Potássio/farmacologia , Coelhos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Guanilil Ciclase Solúvel , Vasoconstrição/efeitos dos fármacosRESUMO
In the present study, a series of original alaninamide derivatives have been designed applying a combinatorial chemistry approach, synthesized, and characterized in the in vivo and in vitro assays. The obtained molecules showed potent and broad-spectrum activity in basic seizure models, namely, the maximal electroshock (MES) test, the 6 Hz (32 mA) seizure model, and notably, the 6 Hz (44 mA) model of pharmacoresistant seizures. Most potent compounds 26 and 28 displayed the following pharmacological values: ED50 = 64.3 mg/kg (MES), ED50 = 15.6 mg/kg (6 Hz, 32 mA), ED50 = 29.9 mg/kg (6 Hz, 44 mA), and ED50 = 34.9 mg/kg (MES), ED50 = 12.1 mg/kg (6 Hz, 32 mA), ED50 = 29.5 mg/kg (6 Hz, 44 mA), respectively. Additionally, 26 and 28 were effective in the ivPTZ seizure threshold test and had no influence on the grip strength. Moreover, lead compound 28 was tested in the PTZ-induced kindling model, and then, its influence on glutamate and GABA levels in the hippocampus and cortex was evaluated by the high-performance liquid chromatography (HPLC) method. In addition, 28 revealed potent efficacy in formalin-induced tonic pain, capsaicin-induced pain, and oxaliplatin- and streptozotocin-induced peripheral neuropathy. Pharmacokinetic studies and in vitro ADME-Tox data proved favorable drug-like properties of 28. The patch-clamp recordings in rat cortical neurons showed that 28 at a concentration of 10 µM significantly inhibited fast sodium currents. Therefore, 28 seems to be an interesting candidate for future preclinical development in epilepsy and pain indications.