RESUMO
Orphanin FQ/nociceptin (OFQ/N) is the endogenously occurring peptide ligand for the nociceptin opioid receptor (NOP) that produces anxiolytic-like effects in mice and rats. The present study assessed the anxiolytic-like activity of 8-[bis(2-methylphenyl)-methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510), a novel potent piperidine NOP agonist (EC(50) = 12 nM) that binds with high affinity (K(i) = 0.3 nM) and functional selectivity (>50-fold over the mu-, kappa-, and delta-opioid receptors). The anxiolytic-like activity and side-effect profile of SCH 221510 were assessed in a variety of models and the benzodiazepine, chlordiazepoxide (CDP), was included for comparison. The effects of chronic dosing of SCH 221510 were also assessed. Furthermore, the specificity of the anxiolytic-like effect of SCH 221510 was investigated with the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and the opioid receptor antagonist naltrexone. Like CDP (1-30 mg/kg i.p.), SCH 221510 (1-30 mg/kg p.o.) produced anxiolytic-like effects in the elevated plus-maze (rat and gerbil), Vogel conflict (rat), conditioned lick suppression (rat), fear-potentiated startle (rat), and pup separation-induced vocalization (guinea pig) assays. In the Vogel conflict, the anxiolytic-like effect of SCH 221510 (10 mg/kg) was attenuated by J-113397 (3-10 mg/kg p.o.), but not naltrexone (3-30 mg/kg i.p.). Additionally, the anxiolytic-like effects of SCH 221510 did not change appreciably following 14-day b.i.d. dosing in rats (10 mg/kg). Furthermore, unlike CDP, SCH 221510 (3-30 mg/kg) produced anxiolytic-like activity at doses that did not disrupt overt behavior. Collectively, these data suggest that NOP agonists such as SCH 221510 may have an anxiolytic-like profile similar to benzodiazepines, with a reduced side-effect liability.
Assuntos
Ansiolíticos/farmacologia , Compostos Azabicíclicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Receptores Opioides/agonistas , Animais , Animais Recém-Nascidos , Ansiolíticos/química , Compostos Azabicíclicos/química , Benzimidazóis/farmacologia , Células CHO , Cricetinae , Cricetulus , Feminino , Gerbillinae , Cobaias , Humanos , Masculino , Estrutura Molecular , Antagonistas de Entorpecentes , Piperidinas/farmacologia , Ligação Proteica , Ratos , Ratos Wistar , Receptores Opioides/metabolismo , Receptor de NociceptinaRESUMO
A series of novel five-membered urea derivatives as potent NK1 receptor antagonists is described. The effects of substitution of a 4-fluoro group at the phenyl ring and the introduction of an alpha-methyl group at the benzylic position to improve potency and duration of in vivo activity are discussed. Several compounds with high affinity and sustained in vivo activity were identified.
Assuntos
Ansiolíticos/química , Ansiolíticos/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Ansiolíticos/síntese química , Álcoois Benzílicos/química , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Flúor/química , Gerbillinae , Modelos Moleculares , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Relação Estrutura-Atividade , Ureia/síntese químicaRESUMO
A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Ureia/análogos & derivados , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Gerbillinae , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/farmacologia , Atividade Motora/efeitos dos fármacos , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
In search of a backup M(2) muscarinic receptor antagonist to the previously reported compound 1, we discovered compound (+)-14, which showed superior oral efficacy in animal models. The improvement of oral efficacy was achieved by modulating both the molecular weight and lipophilicity of the lead compounds.
Assuntos
Autorreceptores/antagonistas & inibidores , Fármacos do Sistema Nervoso Central/síntese química , Antagonistas Muscarínicos/síntese química , Piperidinas/síntese química , Receptores Muscarínicos/efeitos dos fármacos , Acetilcolina/metabolismo , Administração Oral , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/química , Fármacos do Sistema Nervoso Central/farmacologia , Corpo Estriado/metabolismo , Humanos , Técnicas In Vitro , Microdiálise , Conformação Molecular , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Ratos , Receptor Muscarínico M2 , Relação Estrutura-AtividadeRESUMO
We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.
Assuntos
Benzamidas/química , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacocinética , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Acetilcolina/análise , Acetilcolina/biossíntese , Animais , Área Sob a Curva , Benzamidas/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Microdiálise , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Receptores Muscarínicos/metabolismo , Relação Estrutura-AtividadeRESUMO
Several neurokinin NK1 receptor antagonists currently being developed for anxiety and depression have reduced affinity for the rat and mouse NK1 receptor compared with human. Consequently, it has proven difficult to test these agents in traditional rat and mouse models of anxiety and depression. This issue has been overcome, in part, by using non-traditional lab species such as the guinea pig and gerbil, which have NK1 receptors closer in homology to human NK1 receptors. However, there are very few reports describing the behavior of gerbils in traditional models of anxiety. The aim of the present study was to determine if the elevated plus-maze, a commonly used anxiety model, could be adapted for the gerbil. Using a specially-designed elevated plus-maze, gerbils exhibited an 'anxious' behavioral profile similar to that observed in rats and mice, i.e., reduced entries into, and time spent exploring, an open, aversive arm. The anxiolytic drugs diazepam (0.03-3 mg/kg i.p.), chlordiazepoxide (0.3-10 mg/kg i.p.), and buspirone (0.3-30 mg/kg s.c.) increased open arm exploration and produced anxiolytic-like effects on risk-assessment behaviors (reduced stretch-attend postures and increased head dips). Of particular interest, the antidepressant drugs imipramine (1-30 mg/kg p.o.), fluoxetine (1-30 mg/kg, p.o.) and paroxetine (0.3-10 mg/kg p.o.) each produced some acute anxiolytic-like activity, without affecting locomotor activity. The antipsychotic, haloperidol, and the psychostimulant, amphetamine, did not produce any anxiolytic-like effects (1-10 mg/kg s.c). The anxiogenic beta-carboline, FG-7142, reduced time spent in the open arm and head dips, and increased stretch-attend postures (1-30 mg/kg, i.p.). These studies have demonstrated that gerbils exhibit an anxiety-like profile on an elevated plus-maze, and that the gerbil elevated plus-maze may have predictive validity for anxiolytics, and antidepressants with potential anxiolytic-like effects.
Assuntos
Comportamento Animal/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Inibidores da Captação Adrenérgica/farmacologia , Anfetamina/farmacologia , Análise de Variância , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Carbolinas/farmacologia , Relação Dose-Resposta a Droga , Estudos de Avaliação como Assunto , Comportamento Exploratório/efeitos dos fármacos , Feminino , Antagonistas GABAérgicos/farmacologia , Gerbillinae , Haloperidol/farmacologia , Testes Psicológicos/normasRESUMO
Neurokinin NK1 receptor antagonists may have therapeutic potential in the treatment of anxiety and depression. Species variants in the NK1 receptor result in reduced affinity of NK1 receptor antagonists at rat and mouse NK1 receptors, making it difficult to test NK1 antagonists in traditional preclinical models of anxiety and depression. Gerbil NK1 receptors are similar in homology to the human NK1 receptor. In a companion article, we described the anxiety-like behavioral profile of gerbils on an adapted elevated plus-maze, and the ability of anxiolytic drugs to produce anti-anxiety effects in the gerbil elevated plus-maze. The aim of the present study was to determine whether oral (p.o.) administration of the NK1 receptor antagonists MK-869, L-742,694, L-733,060, CP-99,994, and CP-122,721 produced anxiolytic-like effects in the gerbil elevated plus-maze. Upon testing, all five NK1 antagonists produced anxiolytic-like effects. MK-869 (0.01-3 mg/kg) was the most potent NK1 antagonist, producing anxiolytic-like effects on percentage of open arm time, percentage of open arm entries, stretch-attend postures, and head dips at 0.03-0.3 mg/kg doses. L-742,694 (1-30 mg/kg) and L-733,060 (1-10 mg/kg) produced anxiolytic-like effects on percentage of open arm time and stretch-attend postures at 3-10 mg/kg doses. CP-99,994 (3-30 mg/kg) only produced an anxiolytic-like effect on stretch-attend postures. CP-122,721 (3-30 mg/kg) produced an anxiolytic-like effect on percentage of open arm time at 30 mg/kg. The order of potency of the NK1 antagonists to increase percentage of open arm time was very similar to their potency to block NK1 agonist-induced foot-tapping. These studies demonstrate that neurokinin NK1 receptor antagonists produce anxiolytic-like effects in a novel gerbil elevated plus-maze, and suggest that this is an appropriate model to test NK1 antagonists for preclinical anxiolytic activity.