RESUMO
An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.
Assuntos
Encéfalo/metabolismo , Canabinoides/agonistas , Carbolinas/química , Carbolinas/farmacologia , Analgésicos/química , Analgésicos/metabolismo , Analgésicos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Carbolinas/metabolismo , Linhagem Celular , Estabilidade de Medicamentos , Humanos , Estrutura Molecular , Dor/tratamento farmacológico , Ratos , SolubilidadeRESUMO
Cannabinoid CB(1) receptor agonists exhibit potent analgesic effects in rodents and humans, but their clinical utility as analgesic drugs is often limited by centrally mediated side effects. We report herein the preparation of N-methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of hCB(1)/hCB(2) dual agonists with attractive physicochemical properties. More specifically, (R)-N,9-dimethyl-N-(4-(methylamino)-4-oxobutyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide, displayed an extremely low level of CNS penetration (Rat Cbr/Cplasma=0.005 or 0.5%) and was devoid of CNS side effects during pharmaco-dynamic testing.
Assuntos
Analgésicos/síntese química , Carbazóis/síntese química , Dor/tratamento farmacológico , Receptor CB1 de Canabinoide/agonistas , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Carbazóis/farmacocinética , Sistema Nervoso Central/metabolismo , Humanos , Dor/metabolismo , Permeabilidade , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/metabolismo , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Purinergic receptor P2X3 has been linked to analgesia in a number of pre-clinical models of pain, and is expressed in the human pain perception pathway. Only few P2X3-selective antagonists have been reported to date. This Letter describes the SAR and in vivo analgesic profile of a novel scaffold of selective P2X3 antagonists.
Assuntos
Analgésicos/síntese química , Dor Crônica/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2/síntese química , Pirimidinonas/síntese química , Pirróis/síntese química , Receptores Purinérgicos P2X3/química , Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Animais , Dor Crônica/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Injeções Espinhais , Injeções Subcutâneas , Antagonistas do Receptor Purinérgico P2/administração & dosagem , Antagonistas do Receptor Purinérgico P2/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/uso terapêutico , Pirróis/administração & dosagem , Pirróis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X3/metabolismo , Bibliotecas de Moléculas PequenasRESUMO
Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.
Assuntos
Amidas/farmacologia , Benzotiazóis/farmacologia , Dor/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Amidas/administração & dosagem , Amidas/química , Animais , Benzotiazóis/administração & dosagem , Benzotiazóis/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Inflamação/tratamento farmacológico , Estrutura Molecular , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Solubilidade , Relação Estrutura-AtividadeRESUMO
We have investigated phenol replacements in a series of diaryl amino piperidine delta opioid agonists. From this study we have demonstrated that the hydroxy functional group can be replaced with a primary amide group, giving enhanced activity at the delta receptor, increased selectivity versus mu and kappa as well as improved in vitro metabolic stability.
Assuntos
Analgésicos/química , Difenilamina/análogos & derivados , Piperidinas/química , Receptores Opioides delta/agonistas , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Difenilamina/síntese química , Difenilamina/química , Difenilamina/farmacologia , Humanos , Microssomos Hepáticos/metabolismo , Piperidinas/síntese química , Piperidinas/farmacologia , Ratos , Receptores Opioides delta/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 1-aminotetralin scaffolds was synthesized via metal-catalyzed ring-opening reactions of heterobicyclic alkenes. Small libraries of amides and amines were made using the amino group of each scaffold as a handle. Screening of these libraries against human opioid receptors led to the identification of (S)-(S)-5.2a as a high-affinity selective mu ligand (IC(50)mu=5 nM, kappa=707 nM, delta=3,795 nM) displaying mu-agonist/antagonist properties due to its partial agonism (EC(50)=2.6 microM; E(max)=18%).
Assuntos
Analgésicos Opioides/síntese química , Analgésicos Opioides/farmacologia , Técnicas de Química Combinatória , Ródio/química , Analgésicos Opioides/química , Catálise , Humanos , Ligantes , Estrutura Molecular , EstereoisomerismoRESUMO
We have investigated a series of phenolic diaryl amino piperidine delta opioid receptor agonists, establishing the importance of the phenol functional group and substitution on the piperdine nitrogen for delta agonist activity and selectivity versus the mu and kappa opioid receptors. This study uncovered compounds with improved agonist potency and selectivity compared to the standard, non-peptidic delta agonist SNC-80. In vivo anti-nociceptive activity of analog 8e in two rodent models is discussed, demonstrating the potential of delta agonists to provide a novel mechanism for pain relief.
Assuntos
Analgésicos/química , Benzamidas/química , Difenilamina/análogos & derivados , Piperidinas/química , Receptores Opioides delta/agonistas , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Benzamidas/síntese química , Benzamidas/farmacologia , Difenilamina/síntese química , Difenilamina/química , Difenilamina/farmacologia , Modelos Animais de Doenças , Camundongos , Piperidinas/síntese química , Piperidinas/farmacologia , Ratos , Receptores Opioides delta/metabolismo , Relação Estrutura-AtividadeRESUMO
The preparation and evaluation of a novel class of CB2 agonists based on a benzimidazole moiety are reported. They showed binding affinities up to 1nM towards the CB2 receptor with partial to full agonist potencies. They also demonstrated good to excellent selectivity (>1000-fold) over the CB1 receptor.
Assuntos
Benzimidazóis/química , Receptor CB2 de Canabinoide/química , Benzimidazóis/síntese química , Ligação Competitiva , Moduladores de Receptores de Canabinoides/química , Canabinoides/química , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Modelos Químicos , Receptor CB1 de Canabinoide/química , Receptores de Canabinoides/química , Relação Estrutura-Atividade , Tecnologia Farmacêutica/métodosRESUMO
Agonists of the cannabinoid receptor 1 (CB1) have been suggested as possible treatments for a range of medical disorders including gastroesophageal reflux disease (GERD). While centrally acting cannabinoid agonists are known to produce psychotropic effects, it has been suggested that the CB1 receptors in the periphery could play a significant role in reducing reflux. A moderately potent and highly lipophilic series of 2-aminobenzamides was identified through focused screening of GPCR libraries. Development of this series focused on improving potency and efficacy at the CB1 receptor, reducing lipophilicity and limiting the central nervous system (CNS) exposure while maintaining good oral absorption. Improvement of the series led to compounds having excellent potency at the CB1 receptor and high levels of agonism, good physical and pharmacokinetic properties, and low penetration into the CNS. A range of compounds demonstrated a dose-dependent inhibition of transient lower esophageal sphincter relaxations in a dog model.
Assuntos
Benzamidas/síntese química , Encéfalo/metabolismo , Refluxo Gastroesofágico/tratamento farmacológico , Receptor CB1 de Canabinoide/agonistas , Administração Oral , Animais , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Benzamidas/farmacocinética , Benzamidas/farmacologia , Disponibilidade Biológica , Linhagem Celular , Cricetinae , Cricetulus , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Cães , Canal de Potássio ERG1 , Esfíncter Esofágico Inferior/efeitos dos fármacos , Esfíncter Esofágico Inferior/fisiologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Humanos , Relaxamento Muscular/efeitos dos fármacos , Pirazinas/síntese química , Pirazinas/farmacocinética , Pirazinas/farmacologia , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-Atividade , Sulfóxidos/síntese química , Sulfóxidos/farmacocinética , Sulfóxidos/farmacologia , Triazóis/síntese química , Triazóis/farmacocinética , Triazóis/farmacologiaRESUMO
The preparation and evaluation of a novel class of CB2 agonists based on a 1,2,3,4-tetrahydropyrrolo[3,4-b]indole moiety are reported. They showed binding affinities up to 4.2 nM toward CB2 with sub-nanomolar EC(50) values. They also showed moderate to good (>350-fold) selectivity over the CB1 receptor.