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1.
Molecules ; 26(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34299443

RESUMO

Although persistent pain is estimated to affect about 20% of the adult population, current treatments have poor results. Polypharmacology, which is the administration of more than one drug targeting on two or more different sites of action, represents a prominent therapeutic approach for the clinical management of persistent pain. Thus, in the drug discovery process the "one-molecule-multiple targets" strategy nowadays is highly recognized. Indeed, multitarget ligands displaying a better antinociceptive activity with fewer side effects, combined with favorable pharmacokinetic and pharmacodynamic characteristics, have already been shown. Multitarget ligands possessing non-opioid/opioid and opioid/opioid mechanisms of action are considered as potential drug candidates for the management of various pain conditions. In particular, dual-target MOPr (mu opioid peptide receptor)/DOPr (delta opioid peptide receptor) ligands exhibit an improved antinociceptive profile associated with a reduced tolerance-inducing capability. The benzomorphan-based compounds LP1 and LP2 belong to this class of dual-target MOPr/DOPr ligands. In the present manuscript, the structure-activity relationships and the pharmacological fingerprint of LP1 and LP2 compounds as suitable drug candidates for persistent pain relief is described.


Assuntos
Benzomorfanos/farmacologia , Dor/tratamento farmacológico , Receptores Opioides delta/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacos , Analgésicos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Benzomorfanos/química , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Humanos , Ligantes , Dor/fisiopatologia , Manejo da Dor/métodos , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade
2.
ACS Chem Neurosci ; 11(7): 999-1005, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32186844

RESUMO

(+)-(2S,6S,11S)- and (-)-(2R,6R,11R)-Benzomorphan derivatives have a different binding affinity for sigma-1 (σ1R) and opioid receptors, respectively. In this study, we describe the synthesis of the (+)-enantiomer [(+)-LP1] of the benzomorphan MOR agonist/DOR antagonist LP1 [(-)-LP1]. The binding affinity of both (+)-LP1 and (-)-LP1 for σ1R and sigma-2 receptor (σ2R) was tested. Moreover, (+)-LP1 opioid receptor binding affinity was also investigated. Finally, (+)-LP1 was tested in a mouse model of inflammatory pain. Our results showed a nanomolar σ1R and binding affinity for (+)-LP1. Both (+)-LP1 and (-)-LP1 elicited a significant analgesic effect in a formalin test. Differently from (-)-LP1, the analgesic effect of (+)-LP1 was not reversed by naloxone, suggesting a σ1R antagonist profile. Furthermore, σ1R agonist PRE-084 was able to unmask the σ1R antagonistic component of the benzomorphan compound. (+)-LP1 could constitute an useful lead compound to develop new analgesics based on mechanisms of action alternative to opioid receptor activation.


Assuntos
Analgésicos/farmacologia , Benzomorfanos/farmacologia , Receptores sigma/antagonistas & inibidores , Analgésicos/química , Analgésicos Opioides/farmacologia , Animais , Benzomorfanos/síntese química , Modelos Animais de Doenças , Camundongos , Dor/tratamento farmacológico , Receptores Opioides/efeitos dos fármacos , Receptores Opioides/metabolismo , Receptores Opioides delta/efeitos dos fármacos , Receptores Opioides delta/metabolismo , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade
3.
Future Med Chem ; 11(11): 1245-1258, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30974972

RESUMO

Aim: Despite the serious side effects, analgesics acting on opioid receptors are still considered the best way to get antinociception. Matrix metalloproteinases, a large family of zinc-dependent proteases implicated in many pathological conditions, such as diabetes and osteoarthritis, are also involved in inflammation and pain. Methodology & results: Looking for evidence of possible interactions of opioid pathways and inflammation mediators, molecular modeling studies of a series of recently developed µ-opioid receptor benzomorphanic agonists together with biological data on pain and inflammation molecular targets, allowed us to hypothesize a possible correlation between µ-opioid receptor system and MMP-9. Conclusion: A new compound, (-)-MML1017, emerged as a possible dual-acting agent able to interact selectively and potently with the two molecular targets.


Assuntos
Analgésicos/farmacologia , Benzomorfanos/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Receptores Opioides mu/agonistas , Analgésicos/química , Benzomorfanos/química , Descoberta de Drogas , Células HEK293 , Humanos , Metaloproteinase 9 da Matriz/química , Inibidores de Metaloproteinases de Matriz/química , Modelos Moleculares
4.
Eur J Med Chem ; 168: 189-198, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30822708

RESUMO

The pivotal role of the stereocenter at the N-substituent of the 6,7-benzomorphan scaffold was investigated combining synthetic and pharmacological approaches. 2R- and 2S-diastereoisomers of the multitarget MOR/DOR antinociceptive ligand LP2 (1) were synthesized and their pharmacological profile was evaluated in in vitro and vivo assays. From our results, 2S-LP2 (5) showed an improved pharmacological profile in comparison to LP2 (1) and 2R-LP2 (4). 2S-LP2 (5) elicited an antinociceptive effect with a 1.5- and 3-times higher potency than LP2 (1) and R-antipode (4), respectively. In vivo effect of 2S-LP2 (5) was consistent with the improved MOR/DOR efficacy profile assessed by radioligand binding assay, to evaluate the opioid receptor affinity, and BRET assay, to evaluate the capability to promote receptor/G-protein and receptor/ß-arrestin 2 interaction. 2S-LP2 (5) was able to activate, with different efficacy, G-protein pathway over ß-arrestin 2, behaving as biased agonist at MOR and mainly at DOR. Considering the therapeutic potential of both multitarget MOR/DOR agonism and functional selectivity over G-protein, the 2S-LP2 (5) biased multitarget MOR/DOR agonist could provide a safer treatment opportunity.


Assuntos
Analgésicos Opioides/farmacologia , Benzomorfanos/farmacologia , Descoberta de Drogas , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Benzomorfanos/síntese química , Benzomorfanos/química , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Dor Nociceptiva/tratamento farmacológico , Medição da Dor , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 155: 492-502, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29908442

RESUMO

Despite the fact that the benzomorphan skeleton has mainly been employed in medicinal chemistry for the development of opioid analgesics, it is a versatile structure. Its stereochemistry, as well as opportune modifications at the phenolic hydroxyl group and at the basic nitrogen, play a pivotal role addressing the benzomorphan-based compounds to a specific target. In this review, we describe the structure activity-relationships (SARs) of benzomorphan-based compounds acting at sigma 1 receptor (σ1R), sigma 2 receptor (σ2R), voltage-dependent sodium channel, N-Methyl-d-Aspartate (NMDA) receptor-channel complex and other targets. Collectively, the SARs data have highlighted that the benzomorphan nucleus could be regarded as a useful template for the synthesis of drug candidates for different targets.


Assuntos
Analgésicos Opioides/farmacologia , Benzomorfanos/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores sigma/antagonistas & inibidores , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Benzomorfanos/síntese química , Benzomorfanos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
6.
Molecules ; 23(3)2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29547588

RESUMO

The opioid pharmacological profile of cis-(-)-N-normetazocine derivatives is deeply affected by the nature of their N-substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N-phenylpropanamido substituent. LP1 derivatives 5a-d and 6a-d were characterized by flexible groups at the N-substituent that allow them to reposition themselves relative to cis-(-)-N-normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays. Among the series, compound 5c, with the best in vitro and in vivo profile, resulted a MOR agonist which displays a KiMOR of 6.1 nM in a competitive binding assay, and an IC50 value of 11.5 nM and an Imax of 72% in measurement of cAMP accumulation in HEK293 cells stably expressing MOR, with a slight lower efficacy than LP1. Moreover, in a mouse model of acute thermal nociception, compound 5c, intraperitoneally administered, exhibits naloxone-reversed antinociceptive properties with an ED50 of 4.33 mg/kg. These results expand our understanding of the importance of N-substituent structural variations in the opioid receptor profile of cis-(-)-N-normetazocine derivatives and identify a new MOR agonist useful for the development of novel opioid analgesics for pain treatment.


Assuntos
Benzomorfanos/administração & dosagem , Benzomorfanos/síntese química , Nociceptividade/efeitos dos fármacos , Receptores Opioides mu/agonistas , Animais , Benzomorfanos/química , Benzomorfanos/farmacologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Injeções Intraperitoneais , Camundongos , Modelos Moleculares , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 148: 410-422, 2018 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29477074

RESUMO

Benzomorphan, derived by morphine skeleton simplification, has been the subject of exploration in medicinal chemistry for the development of new drugs and pharmacological tools to explore opioid pharmacology in vitro and in vivo. Building upon these evidences, the design and synthesis of benzomorphan-based compounds, appropriately modified at the basic nitrogen and/or the phenolic hydroxyl (8-OH) group, represent a valid and versatile strategy to obtain analgesics. In this review, to improve the body of information in this field, we report structure activity-relationships (SARs) of benzomorphan-based compounds analysing data literature of last 25 years. Collectively, SARs data highlighted that the benzomorphan nucleus represents a template in the achievement of a specific functional profile, by modifying N-substituent or 8-OH group.


Assuntos
Analgésicos Opioides/química , Benzomorfanos/química , Química Farmacêutica/métodos , Humanos , Relação Estrutura-Atividade
8.
Bioorg Med Chem ; 25(17): 4745-4752, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28734666

RESUMO

Pain relief achieved by co-administration of drugs acting at different targets is more effective than that obtained with conventional MOR selective agonists usually associated to relevant side effects. It has been demonstrated that simultaneously targeting different opioid receptors is a more effective therapeutic strategy. Giving the promising role for DOR in pain management, novel LP1-based analogues with different N-substituents were designed and synthesized with the aim to improve DOR profile. For this purpose, we maintained the phenyl ring in the N-substituent of 6,7-benzomorphan scaffold linked to an ethyl spacer bearing a hydroxyl/methyl or methoxyl group at carbon 2 or including it in a 1,4-benzodioxane ring. LP1 analogues were tested by competition binding assays. Compounds 6 (KiMOR=2.47nM, KiDOR=9.6nM), 7 (KiMOR=0.5nM and KiDOR=0.8nM) and 9 (KiMOR=1.08nM, KiDOR=6.6nM) retained MOR affinity but displayed an improved DOR binding capacity as compared to LP1 (KiMOR=0.83nM, KiDOR=29.1nM). Moreover, GPI and MVD functional assays indicated that compounds 6 (IC50=49.2 and IC50=10.8nM), 7 (IC50=9.9 and IC50=11.8nM) and 9 (IC50=21.5 and IC50=4.4nM) showed a MOR/DOR agonist profile, unlike LP1 that was a MOR agonist/DOR antagonist (IC50=1.9 and IC50=1240nM). Measurements of their antinociceptive effect was evaluated by mice radiant tail flick test displaying for compounds 6, 7 and 9 ED50 values of 1.3, 1.0 and 0.9mg/kg, i.p., respectively. Moreover, the antinociceptive effect of compound 9 was longer lasting with respect to LP1. In conclusion the N-substituent nature of compounds 6, 7 and 9 shifts the DOR profile of LP1 from antagonism to agonism.


Assuntos
Analgésicos/química , Benzomorfanos/química , Receptores Opioides delta/metabolismo , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Animais , Ligação Competitiva , Concentração Inibidora 50 , Cinética , Masculino , Camundongos , Dor/tratamento farmacológico , Ligação Proteica , Receptores Opioides delta/química , Receptores Opioides kappa/química , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade , Trítio/química
9.
Sci Rep ; 6: 35355, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27752090

RESUMO

DNA methylation is an important epigenetic mark that regulates gene expression. Dnmt1 plays an important role in maintaining DNA methylation patterns on daughter DNA strands. Studies have shed light into the functional role of Dnmt1 regulation in the hematopoietic and epidermal systems. Here we show that Dnmt1 is required for myogenesis. Loss of Dnmt1 results in reduced expression of myogenic genes and defects in myogenic differentiation. We have utilized a conditional knockout mouse approach to examine the functional consequences of Dnmt1 depletion specifically in the developing muscle. These mice were born runted, with smaller body weights, and reduced ability to form myotubes in vitro. We show that expression of Id-1, a negative regulator of myogenesis, is enhanced in Dnmt1-deficient cultures, leading to enhanced transdifferentiation of myoblasts toward the osteogenic lineage. Thus, these studies demonstrate that Dnmt1 influences cellular identity and determines lineage fidelity.


Assuntos
Diferenciação Celular/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , Proteína 1 Inibidora de Diferenciação/genética , Desenvolvimento Muscular/genética , Animais , Benzomorfanos , Linhagem da Célula/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteína 1 Inibidora de Diferenciação/metabolismo , Camundongos , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo
10.
Bioorg Med Chem ; 24(21): 5280-5290, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27624520

RESUMO

The hypothesis that central analgesia with reduced side effects is obtainable by occupying an 'allosteric' site in the MOR ligand binding domain requires the development of new ligands with peculiar pharmacological profile to be used as tools. New benzomorphan derivatives, analogues of LP1, a multitarget MOR agonist/DOR antagonist, were designed to examine in depth MOR ligand binding domain. Compound 5, bearing a diphenylic N-substituent on the benzomorphan nucleus, showed an affinity (Kiµ=0.5±0.2nM) comparable to that of LP1 and a better selectivity versus DOR and KOR. It elicits antinociceptive effects in ex vivo (GPI) and in vivo. This new compound engages receptor amino acidic residues not reached by LP1 and by other established MOR ligands. Molecular modeling studies, conducted on 5 and on several reference compounds, allowed us to propose possible residues in the MOR ligand binding domain essential for their interactions with 'orthosteric' and 'allosteric' binding sites.


Assuntos
Benzomorfanos/farmacologia , Receptores Opioides mu/agonistas , Animais , Benzomorfanos/síntese química , Benzomorfanos/química , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Cobaias , Células HEK293 , Humanos , Íleo/efeitos dos fármacos , Ligantes , Masculino , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
11.
Bioorg Med Chem ; 24(12): 2832-42, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27234885

RESUMO

The benzomorphan scaffold has great potential as lead structure and the nature of the N-substituent is able to influence affinity, potency, and efficacy at all three opioid receptors. Building upon these considerations, we synthesized a new series of LP1 analogues by introducing naphthyl or heteroaromatic rings in propanamide side chain of its N-substituent (9-15). In vitro competition-binding assays in HEK293 cells stably expressing MOR, DOR or KOR showed that in compound 9 the 1-naphthyl ring led to the retention of MOR affinity (Ki(MOR)=38±4nM) displaying good selectivity versus DOR and KOR. In the electrically stimulated GPI, compound 9 was inactive as agonist but produced an antagonist potency value (pA2) of 8.6 in presence of MOR agonist DAMGO. Moreover, subcutaneously administered it antagonized the antinociceptive effects of morphine with an AD50=2.0mg/kg in mouse-tail flick test. Modeling studies on MOR revealed that compound 9 fit very well in the binding pocket but in a different way in respect to the agonist LP1. Probably the replacement of its N-substituent on the III, IV and V TM domains reflects an antagonist behavior. Therefore, compound 9 could represent a potential lead to further develop antagonists as valid therapeutic agents and useful pharmacological tools to study opioid receptor function.


Assuntos
Analgésicos Opioides/química , Analgésicos Opioides/farmacologia , Benzomorfanos/química , Benzomorfanos/farmacologia , Antagonistas de Entorpecentes/química , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides/metabolismo , Animais , Cobaias , Células HEK293 , Humanos , Masculino , Camundongos , Modelos Moleculares , Ratos , Receptores Opioides delta/metabolismo , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/metabolismo
12.
ChemMedChem ; 11(6): 556-61, 2016 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-26915462

RESUMO

A novel structural class with high affinity and subtype selectivity for the sigma 2 receptor has been discovered. Preliminary structure-affinity relationship data are presented showing that 8-substituted 1,3,4,5-tetrahydro-1,5-methanobenzazepine (norbenzomorphan) derivatives elicit modest to high selectivity for the sigma 2 over the sigma 1 receptor subtype. Indeed, piperazine analogue 8-(4-(3-ethoxy-3-oxopropyl)piperazin-1-yl)-1,3,4,5-tetrahydro-1,5-methanobenzazepine-2-carboxylate (SAS-1121) is 574-fold selective for the sigma 2 over the sigma 1 receptor, thereby establishing it as one of the more subtype-selective sigma 2 binding ligands reported to date. Emerging evidence has implicated the sigma 2 receptor in multiple health disorders, so the drug-like characteristics of many of the selective sigma 2 receptor ligands disclosed herein, coupled with their structural similarity to frameworks found in known drugs, suggest that norbenzomorphan analogues may be promising candidates for further development into drug leads.


Assuntos
Benzazepinas/farmacologia , Benzomorfanos/química , Proteínas de Membrana/metabolismo , Piperazinas/farmacologia , Receptores de Progesterona/metabolismo , Receptores sigma/metabolismo , Animais , Benzazepinas/síntese química , Benzazepinas/química , Benzomorfanos/síntese química , Benzomorfanos/farmacologia , Cobaias , Ligantes , Piperazinas/síntese química , Piperazinas/química , Ensaio Radioligante , Ratos , Estereoisomerismo
13.
J Chem Inf Model ; 55(3): 614-27, 2015 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-25642595

RESUMO

Human kappa opioid receptor (κ-OR), a G protein-coupled receptor (GPCR), has been identified as a drug target for treatment of such human disorders as pain perception, neuroendocrine physiology, affective behavior, and cognition. In order to find more selective and active agonists, one would like to do structure based drug design. Indeed, there is an X-ray structure for an antagonist bound to κ-OR, but structures for activated GPCRs are quite different from those for the inactive GPCRs. Here we predict the ensemble of 24 low-energy structures of human kappa opioid receptor (κ-OR), obtained by application of the GEnSeMBLE (GPCR Ensemble of Structures in Membrane Bilayer Environment) complete sampling method, which evaluates 13 trillion combinations of tilt and rotation angles for κ-OR to select the best 24. To validate these structures, we used the DarwinDock complete sampling method to predict the binding sites for five known agonists (ethylketocyclazocine, bremazocine, pentazocine, nalorphine, and morphine) bound to all 24 κ-OR conformations. We find that some agonists bind selectively to receptor conformations that lack the salt bridge between transmembrane domains 3 and 6 as expected for active conformations. These 3D structures for κ-OR provide a structural basis for understanding ligand binding and activation of κ-OR, which should be useful for guiding subtype specific drug design.


Assuntos
Modelos Moleculares , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/química , Benzomorfanos/metabolismo , Benzomorfanos/farmacologia , Sítios de Ligação , Desenho de Fármacos , Etilcetociclazocina/metabolismo , Humanos , Ligantes , Simulação de Acoplamento Molecular , Morfina/metabolismo , Morfina/farmacologia , Nalorfina/metabolismo , Nalorfina/farmacologia , Pentazocina/metabolismo , Pentazocina/farmacologia , Conformação Proteica , Receptores Acoplados a Proteínas G/química , Receptores Opioides kappa/metabolismo , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 77: 84-90, 2014 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-24631726

RESUMO

An emerging approach in pain management is the use of multitarget opioid ligands, owing an improved analgesic effect coupled to a reduced incidence of side effects. With a mu opioid receptor agonist/delta opioid receptor antagonist profile, the benzomorphan-based compound LP1 belongs to multitarget ligands class. Previous in vivo investigations showed that LP1 - subcutaneously administered as oxalate salt - was an antinociceptive agent as potent as morphine with a low tolerance-inducing capability. Because the renal toxicity of oxalate is known, an alternative approach allowing the administration of LP1 freebase could be more biocompatible. In this study the interaction of LP1 freebase and LP1 oxalate salt with multilamellar vesicles, as membrane model, was evaluated using differential scanning calorimetry technique. Despite the good membrane interaction showed by LP1 freebase, it was not capable to diffuse in the aqueous medium and to be uptaken by multilamellar vesicles. On the other hand, LP1 freebase possessed a good transfer profile by a liposomal carrier to a biomembrane model. Considering our findings and the need of safe formulations, studies for the development of a suitable carrier for a systemic administration of LP1 freebase are in progress.


Assuntos
Benzomorfanos/química , Lipossomos/química , Varredura Diferencial de Calorimetria , Células Eucarióticas/química , Bicamadas Lipídicas/química , Modelos Biológicos , Estrutura Molecular , Fosfolipídeos/química
15.
Eur J Pharmacol ; 731: 1-7, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24657279

RESUMO

Several methodological approaches suggest that receptor heteromers exist in cell systems, but their presence in physiological tissue is widely contentious. We describe a novel method to determine if heterodimers exist in brain tissue sections using autoradiographic binding comparisons from single and double gene knockout mice, where tissues either have a full receptor complement and can form heterodimers, or are incapable of making heterodimers. We have tested this model, which we have named Knockout Subtraction Autoradiography, to determine if heterodimerisation of the kappa (KOP) and delta opioid (DOP) receptors occurs, as evidence from binding studies in cell systems suggest they are present in the brain. Using labeling of putative KOP receptor/DOP receptor heterodimers with either [(3)H]bremazocine or with [(3)H]naltrindole, two ligands which were used to provide evidence suggesting that these opioid receptor subtypes heterodimerize, we have applied a subtraction equation model based on the principle that receptor gene double knockout of either MOP receptor/KOP receptor (DOP receptor expression only) or MOP receptor/DOP receptor (KOP receptor expression only) produces tissue incapable of making the KOP receptor/DOP receptor heterodimer. We have shown in most brain regions that the labeling fits a simple additive model of monomer labeling, but that in a few brain regions opioid receptor heterodimerization does occur. The data does not support the conclusion that KOP receptor/DOP receptor heterodimerisation is widespread in the central nervous system, but does indicate that this novel methodology can detect heterodimerisation, when ligands with distinct binding affinities for monomer and heterodimer forms exist.


Assuntos
Autorradiografia/métodos , Encéfalo/metabolismo , Técnicas de Inativação de Genes , Multimerização Proteica , Receptores Opioides delta/química , Receptores Opioides kappa/química , Técnica de Subtração , Animais , Benzomorfanos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Naltrexona/análogos & derivados , Naltrexona/metabolismo , Estrutura Quaternária de Proteína , Receptores Opioides delta/deficiência , Receptores Opioides delta/genética , Receptores Opioides kappa/deficiência , Receptores Opioides kappa/genética
16.
Neuropharmacology ; 71: 70-82, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23541722

RESUMO

Persistent pain states, such as those caused by nerve injury or inflammation, are associated with altered sensations, allodynia and hyperalgesia, that are resistant to traditional analgesics. A contribution to development and maintenance in altered pain perception comes from nociceptive processing and descending modulation from supraspinal sites. A multitarget ligand seems to be useful for pain relief with a decreased risk of adverse events and a considerable analgesic efficacy. The multitarget MOR agonist-DOR antagonist LP1, (3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benazocin-3(2H)-yl]-N-phenylpropanamide, is a central acting antinociceptive agent with low potential to induce tolerance. LP1 was tested in models of neuropathic pain - induced by chronic constriction injury (CCI) of the left sciatic nerve - and inflammatory pain - produced by intraplantar injection of carrageenan. In CCI rats, subcutaneous (s.c.) LP1 (3 mg/kg) showed a significant antiallodynic effect, measured with von Frey filaments, and antihyperalgesic effect, evoked in response to a radiant heat stimulus with plantar test. Analogously, LP1 significantly reduced allodynic and hyperalgesic thresholds in a model of inflammatory pain induced by carrageenan. To evaluate the contribution of opioid receptor subtypes in LP1 antinociceptive effects, the multitarget LP1 profile was assessed using selective opioid antagonists. Moreover, functional electrophysiological in vitro assays, using primary cortical and spinal cord networks, allowed to define the "pharmacological fingerprint" of LP1. The EC50 values in this functional screening seem to confirm LP1 as a potent opioid ligand (EC50 = 0.35 fM and EC50 = 44 pM in spinal cord and frontal cortex, respectively). Using a NeuroProof data-base of well characterised reference compounds, a similarity profile of LP1 to opioid and non-opioid drugs involved in pain modulation was detected. Our studies seem to support that multitarget ligand approach should be useful for persistent pain conditions in which mechanical allodynia and thermal hyperalgesia are significant components of the nociceptive response.


Assuntos
Analgésicos Opioides/uso terapêutico , Benzomorfanos/uso terapêutico , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Proteínas do Tecido Nervoso/metabolismo , Neuralgia/tratamento farmacológico , Neurônios/efeitos dos fármacos , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Animais , Benzomorfanos/metabolismo , Benzomorfanos/farmacologia , Células Cultivadas , Dor Crônica/imunologia , Dor Crônica/metabolismo , Embrião de Mamíferos , Lobo Frontal/citologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/imunologia , Lobo Frontal/metabolismo , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neuralgia/imunologia , Neuralgia/metabolismo , Neurônios/citologia , Neurônios/imunologia , Neurônios/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides delta/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/metabolismo
17.
ACS Comb Sci ; 14(9): 496-502, 2012 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-22857149

RESUMO

A 124-member norbenzomorphan library has been prepared utilizing a novel multicomponent assembly process (MCAP) followed by a variety of ring-closing reactions to generate norbenzomorphan scaffolds that were readily derivatized via a series of aryl halide cross-coupling and nitrogen functionalization reactions. Biological screening has revealed some novel activities that have not been previously associated with this class of compounds.


Assuntos
Benzomorfanos/síntese química , Técnicas de Química Combinatória/métodos , Benzomorfanos/química , Benzomorfanos/farmacologia , Descoberta de Drogas , Humanos , Nitrogênio/química
18.
J Pharm Pharmacol ; 64(8): 1084-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22775211

RESUMO

OBJECTIVES: The aim of this study was to determine whether Ca(2+)-activated Cl(-) channels (CaCCs) are involved in central antinociception induced by the activation of µ-, δ- and κ-opioid receptors. METHODS: The nociceptive threshold for thermal stimulation was measured using the tail-flick test in Swiss mice. The drugs were administered via the intracerebroventricular route. Probabilities values of P < 0.05 were considered to be statistically significant (analysis of variance/Bonferroni test). KEY FINDINGS: The results demonstrate that exposure to the CaCC blocker niflumic acid (2, 4 and 8 µg) partially reverses the central antinociception induced by the δ-opioid receptor agonist SNC80 ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide; 4 µg). In contrast, niflumic acid did not modify the antinociceptive effect of the µ-opioid receptor agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (0.5 µg) or κ-opioid receptor agonist bremazocine (4 µg). CONCLUSIONS: These data provide evidence for the involvement of CaCCs in δ-opioid receptor-induced central antinociception resulting from receptor activation by the agonist SNC80. CaCC activation does not appear to be involved when µ- and κ-opioid receptors are activated.


Assuntos
Analgésicos Opioides/farmacologia , Benzamidas/farmacologia , Cálcio/metabolismo , Canais de Cloreto/metabolismo , Dor/tratamento farmacológico , Piperazinas/farmacologia , Receptores Opioides delta/agonistas , Analgésicos Opioides/uso terapêutico , Animais , Benzamidas/uso terapêutico , Benzomorfanos/farmacologia , Cátions/metabolismo , Encefalinas/farmacologia , Temperatura Alta , Masculino , Camundongos , Camundongos Endogâmicos , Ácido Niflúmico/farmacologia , Dor/metabolismo , Limiar da Dor/efeitos dos fármacos , Piperazinas/uso terapêutico , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas
19.
Life Sci ; 90(25-26): 957-61, 2012 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-22580287

RESUMO

AIMS: Opioid drugs are the principal treatment option for moderate to severe pain and exert their biological effects through interactions with opioid receptors that are widely distributed throughout the CNS and peripheral tissues. Ligands capable of simultaneously targeting different receptors could be successful candidates for the treatment of chronic pain. Enhanced antinociception coupled with a low incidence of side effects has been demonstrated for ligands possessing mixed mu-opioid receptor (MOR) and delta-opioid receptor (DOR) activity. We previously reported that 3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide (LP1) acted as a MOR-DOR ligand in in vitro functional assays and moreover this drug produced a valid antinociception that was longer lasting than that of morphine. The aim of this work was to determine whether the antinociceptive effect produced by LP1 was central or peripheral and to assess which opioid receptor subtypes are involved in its effects. MAIN METHODS: We explored the effects of naloxone methiodide (NX-M), a quaternary opioid antagonist, administered either intracerebroventricularly (i.c.v.) or subcutaneously (s.c.), on LP1-mediated antinociception in male Sprague-Dawley rats. In addition, we administered s.c. selective antagonists for MOR, DOR and kappa-opioid receptor (KOR) to investigate the effects of LP1. To characterise this drug's DOR profile better, we also investigated the effects of LP1 on DPDPE, a selective DOR agonist. KEY FINDINGS: Data obtained by tail flick test showed that LP1 induced predominantly MOR-mediated supraspinal antinociception and was able to counteract DPDPE analgesia. SIGNIFICANCE: LP1, a multitarget opioid ligand, is a supraspinal acting antinociceptive agent that is useful for the treatment of chronic pain.


Assuntos
Analgésicos/administração & dosagem , Benzomorfanos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Medição da Dor/efeitos dos fármacos , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Analgésicos/metabolismo , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/metabolismo , Animais , Benzomorfanos/metabolismo , Ligantes , Masculino , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Reprodutibilidade dos Testes
20.
Life Sci ; 90(1-2): 66-70, 2012 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-22100511

RESUMO

AIMS: Powerful analgesics relieve pain primarily through activating mu opioid receptor (MOR), but the long-term use of MOR agonists, such as morphine, is limited by the rapid development of tolerance. Recently, it has been observed that simultaneous stimulation of the delta opioid receptor (DOR) and MOR limits the incidence of tolerance induced by MOR agonists. 3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide (LP1) is a centrally acting agent with antinociceptive activity comparable to morphine and is able to bind and activate MOR and DOR. The aim of this work was to evaluate and compare the induction of tolerance to antinociceptive effects from treatment with LP1 and morphine. MAIN METHODS: Here, we evaluated the pharmacological effects of LP1 administered at a dose of 4 mg/kg subcutaneously (s.c.) twice per day for 9 days to male Sprague-Dawley rats. In addition, the LP1 mechanism of action was assessed by measurement of LP1-induced [(35)S]GTPγS binding to the MOR and DOR. KEY FINDINGS: Data obtained from the radiant heat tail flick test showed that LP1 maintained its antinociceptive profile until the ninth day, while tolerance to morphine (10mg/kg s.c. twice per day) was observed on day 3. Moreover, LP1 significantly enhanced [(35)S]GTPγS binding in the membranes of HEK293 cells expressing either the MOR or the DOR. SIGNIFICANCE: LP1 is a novel analgesic agent for chronic pain treatment, and its low tolerance-inducing capability may be correlated with its ability to bind both the MOR and DOR.


Assuntos
Analgésicos Opioides/uso terapêutico , Benzomorfanos/uso terapêutico , Dor Crônica/tratamento farmacológico , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Animais , Benzomorfanos/metabolismo , Benzomorfanos/farmacologia , Tolerância a Medicamentos/fisiologia , Células HEK293 , Humanos , Ligantes , Masculino , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Resultado do Tratamento
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