RESUMO
A novel series of diphenyl lactam containing calcium channel blockers is described. Extensive SAR studies resulted in compounds with low molar activity and good plasma exposure after oral dosing. Compounds 2, 6 and 7 demonstrated significant efficacy in the capsaicin model of secondary hyperalgesia following oral administration.
Assuntos
Compostos de Bifenilo/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio Tipo N/metabolismo , Descoberta de Drogas , Lactamas/síntese química , Administração Oral , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacocinética , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Concentração Inibidora 50 , Lactamas/química , Lactamas/farmacocinética , Estrutura Molecular , Piperazinas/química , Ratos , SolubilidadeRESUMO
Blockade of voltage-gated Ca²âº channels on sensory nerves attenuates neurotransmitter release and membrane hyperexcitability associated with chronic pain states. Identification of small molecule Ca²âº channel blockers that produce significant antinociception in the absence of deleterious hemodynamic effects has been challenging. In this report, two novel structurally related compounds, A-686085 and A-1048400, were identified that potently block N-type (IC50=0.8 µM and 1.4 µM, respectively) and T-type (IC50=4.6 µM and 1.2 µM, respectively) Ca²âº channels in FLIPR based Ca²âº flux assays. A-686085 also potently blocked L-type Ca²âº channels (EC50=0.6 µM), however, A-1048400 was much less active in blocking this channel (EC50=28 µM). Both compounds dose-dependently reversed tactile allodynia in a model of capsaicin-induced secondary hypersensitivity with similar potencies (EC50=300-365 ng/ml). However, A-686085 produced dose-related decreases in mean arterial pressure at antinociceptive plasma concentrations in the rat, while A-1048400 did not significantly alter hemodynamic function at supra-efficacious plasma concentrations. Electrophysiological studies demonstrated that A-1048400 blocks native N- and T-type Ca²âº currents in rat dorsal root ganglion neurons (IC50=3.0 µM and 1.6 µM, respectively) in a voltage-dependent fashion. In other experimental pain models, A-1048400 dose-dependently attenuated nociceptive, neuropathic and inflammatory pain at doses that did not alter psychomotor or hemodynamic function. The identification of A-1048400 provides further evidence that voltage-dependent inhibition of neuronal Ca²âº channels coupled with pharmacological selectivity vs. L-type Ca²âº channels can provide robust antinociception in the absence of deleterious effects on hemodynamic or psychomotor function.
Assuntos
Analgésicos/administração & dosagem , Bloqueadores dos Canais de Cálcio/administração & dosagem , Hemodinâmica/fisiologia , Neurônios/fisiologia , Medição da Dor , Piperidonas/administração & dosagem , Piperidonas/química , Administração Oral , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Neurônios/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-DawleyRESUMO
Fatty acid amide hydrolase (FAAH) is the primary regulator of several bioactive lipid amides including anandamide. Inhibitors of FAAH are potentially useful for the treatment of pain, anxiety, depression, and other nervous system disorders. However, FAAH inhibitors must display selectivity for this enzyme relative to the numerous other serine hydrolases present in the human proteome in order to be therapeutically acceptable. Here we employed activity-based protein profiling (ABPP) to assess the selectivity of FAAH inhibitors in multiple rat and human tissues. We discovered that some inhibitors, including carbamate compounds SA-47 and SA-72, and AM404 are exceptionally selective while others, like URB597, BMS-1, OL-135, and LY2077855 are less selective, displaying multiple off-targets. Since proteins around 60kDa constitute the major off-targets for URB597 and several other FAAH inhibitors with different chemical structures, we employed the multi-dimensional protein identification technology (MudPIT) approach to analyze their identities. We identified multiple carboxylesterase isozymes as bona fide off-targets of FAAH inhibitors. Consistently, enzymatic assay confirmed inhibition of carboxylesterase activities in rat liver by FAAH inhibitors. Since carboxylesterases hydrolyze a variety of ester-containing drugs and prodrugs, we speculate that certain FAAH inhibitors, by inhibiting carboxylesterases, might have drug-drug interactions with other medicines if developed as therapeutic agents.
Assuntos
Amidoidrolases/antagonistas & inibidores , Benzamidas/farmacologia , Carbamatos/farmacologia , Carboxilesterase/metabolismo , Inibidores Enzimáticos/farmacologia , Amidoidrolases/química , Amidoidrolases/imunologia , Animais , Anticorpos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Coração/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Proteoma/efeitos dos fármacos , Proteoma/metabolismo , Ratos , Transfecção/métodosRESUMO
A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D4 agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor agonists.
Assuntos
Disfunção Erétil/tratamento farmacológico , Oximas/farmacologia , Piperazinas/farmacologia , Receptores de Dopamina D4/agonistas , Animais , Benzamidas/química , Benzamidas/farmacologia , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Furões , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Oximas/síntese química , Oximas/química , Piperazinas/síntese química , Piperazinas/química , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We have discovered a novel, potent, and selective triazafluorenone series of metabotropic glutamate receptor 1 (mGluR1) antagonists with efficacy in various rat pain models. Pharmacokinetic and pharmacodynamic profiles of these triazafluorenone analogs revealed that brain/plasma ratios of these mGluR1 antagonists were important to achieve efficacy in neuropathic pain models. This correlation could be used to guide our in vivo SAR (structure-activity relationship) modification. For example, compound 4a has a brain/plasma ratio of 0.34, demonstrating only moderate efficacy in neuropathic pain models. On the other hand, antagonist 4b with a brain/plasma ratio of 2.70 was fully efficacious in neuropathic pain models.
Assuntos
Compostos Aza/síntese química , Compostos Aza/farmacologia , Encéfalo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Dor/tratamento farmacológico , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Compostos Aza/sangue , Compostos Aza/química , Encéfalo/metabolismo , Linhagem Celular , Humanos , Modelos Animais , Estrutura Molecular , Dor/metabolismo , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
The dopamine D4 receptor has been investigated for its potential role in several CNS disorders, notably schizophrenia and more recently, erectile dysfunction. Whereas studies have investigated dopamine D4 receptor-mediated signaling in vitro, there have been few, if any, attempts to identify dopamine D4 receptor signal transduction pathways in vivo. In the present studies, the selective dopamine D4 agonist PD168077 induces c-Fos expression and extracellular signal regulated kinase (ERK) phosphorylation in the hypothalamic paraventricular nucleus (PVN), a site known to regulate proerectile activity. The selective dopamine D4 receptor antagonist A-381393 blocked both c-Fos expression and ERK1/2 phosphorylation produced by PD168077. In addition, PD168077-induced ERK1/2 phosphorylation was prevented by SL327, an inhibitor of ERK1/2 phosphorylation. Interestingly, treatment with A-381393 alone significantly reduced the amount of Fos immunoreactivity as compared to basal expression observed in vehicle-treated controls. Dopamine D4 receptor and c-Fos coexpression in the PVN was observed using double immunohistochemical labeling, suggesting that PD168077-induced signaling may result from direct dopamine D4 receptor activation. Our results demonstrate functional dopamine D4 receptor expression and natural coupling in the PVN linked to signal transduction pathways that include immediate early gene and MAP kinase activation. Further, the ability of the selective dopamine D4 antagonist A-381393 alone to reduce c-Fos expression below control levels may imply the presence of a tonic dopamine D4 receptor activation under basal conditions in vivo. These findings provide additional evidence that the PVN may be a site of dopamine D4 receptor-mediated proerectile activity.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Genes fos/fisiologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores de Dopamina D4/fisiologia , Transdução de Sinais/fisiologia , Aminoacetonitrila/análogos & derivados , Aminoacetonitrila/farmacologia , Animais , Benzamidas/farmacologia , Benzimidazóis/farmacologia , Contagem de Células/métodos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica/métodos , Masculino , Fosforilação/efeitos dos fármacos , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D4/agonistas , Receptores de Dopamina D4/antagonistas & inibidores , Fatores de TempoRESUMO
SAR (structure-activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists. Compound 1n, for example, was a very potent mGluR1 antagonist (IC50 = 3 nM) and demonstrated full efficacy in various in vivo animal pain models.
Assuntos
Analgésicos/síntese química , Compostos Aza/síntese química , Fluorenos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Analgésicos/química , Analgésicos/farmacologia , Animais , Compostos Aza/química , Compostos Aza/farmacologia , Cálcio/metabolismo , Linhagem Celular , Cerebelo/metabolismo , Fluorenos/química , Fluorenos/farmacologia , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Masculino , Medição da Dor , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 3-aryl piperidine analogs with 2-piperidinoalkylamino or 2-piperidinoalkyloxy fused bicyclic rings were prepared and found to be potent and efficacious human dopamine D4 agonists. The synthesis and structure-activity relationship (SAR) studies that led to the identification of these compounds are discussed.
Assuntos
Agonistas de Dopamina/síntese química , Agonistas de Dopamina/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores de Dopamina D2/agonistas , Linhagem Celular , Agonistas de Dopamina/química , Humanos , Ligantes , Estrutura Molecular , Piperidinas/síntese química , Receptores de Dopamina D4 , Relação Estrutura-AtividadeRESUMO
A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.
Assuntos
Benzimidazóis/síntese química , Disfunção Erétil/tratamento farmacológico , Piperazinas/síntese química , Piridinas/síntese química , Receptores de Dopamina D2/agonistas , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/toxicidade , Linhagem Celular , Furões , Humanos , Masculino , Ereção Peniana/efeitos dos fármacos , Piperazinas/química , Piperazinas/farmacologia , Piperazinas/toxicidade , Piridinas/química , Piridinas/farmacologia , Piridinas/toxicidade , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de Dopamina D4 , Relação Estrutura-Atividade , Vômito/induzido quimicamenteRESUMO
Structure-activity studies were performed on the alpha(1A)-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the alpha(1A), alpha(1b), alpha(1d), alpha(2a), and alpha(2B) subtypes. Functional activity in tissues containing the alpha(1A) (rabbit urethra), alpha(1B) (rat spleen), alpha(1D) (rat aorta), and alpha(2A) (rat prostatic vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the compounds. Many of the compounds that were highly selective in vitro for the alpha(1A)-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselective alpha(1)-agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater alpha(1A) selectivity would reduce cardiovascular side effects. However, the data also support a prominent role of the alpha(1A)-AR subtype in the control of MAP.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 1 , Imidazóis/síntese química , Naftalenos/síntese química , Sulfonamidas/síntese química , Tetra-Hidronaftalenos/síntese química , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Cães , Feminino , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Naftalenos/química , Naftalenos/farmacologia , Coelhos , Ensaio Radioligante , Ratos , Receptores Adrenérgicos alfa 1 , Baço/efeitos dos fármacos , Baço/fisiologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologia , Uretra/efeitos dos fármacos , Uretra/fisiologia , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/fisiologiaRESUMO
A series of subtype selective dopamine D(4) receptor ligands from the hetroarylmethylphenylpiperazine class have been discovered that exhibit a remarkable structure-activity relationship (SAR), revealing a substituent effect in which regiosubstitution on the terminal arylpiperazine ring can modulate functional or intrinsic activity. Other structure-dependent efficacy studies in the dopamine D(4) field have suggested a critical interaction of the heteroarylmethyl moiety with specific protein microdomains in controlling intrinsic activity. Our studies indicate that for some binding orientations, the phenylpiperazine moiety also plays a key role in determining efficacy. These data also implicate a kinetic or efficiency term, contained within measured functional affinities for agonists, which support a sequential binding and conformational stabilization model for receptor activation. The structural similarity between partial agonist and antagonist, within this subset of ligands, and lack of bioisosterism for this substituent effect are key phenomena for these hypotheses.