RESUMO
We designed and synthesized a series of dihydroquinazolinone derivatives as selective M1 and M4 muscarinic acetylcholine receptors agonists. Introduction of the N-carbethoxy piperidine unit into a HTS hit compound followed by optimization of the amine linker and the carbamoyl moiety led to the identification of compound 1 as a potential candidate. The identified compound 1 showed high selectivity for M1 and M4 muscarinic acetylcholine receptors with M4 partial agonistic activity. In addition, compound 1 showed good brain penetration and reversed methamphetamine-induced hyperlocomotion in rats (ED50=3.0 mg/kg, sc).
Assuntos
Descoberta de Drogas , Agonistas Muscarínicos/farmacocinética , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M4/agonistas , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Estrutura Molecular , Agonistas Muscarínicos/síntese química , Agonistas Muscarínicos/farmacologia , Ligação Proteica/efeitos dos fármacos , RatosRESUMO
We designed and synthesized novel N-sulfonyl-7-azaindoline derivatives as selective M4 muscarinic acetylcholine receptor agonists. Modification of the N-carbethoxy piperidine moiety of compound 2, an M4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound 1, a selective M4 mAChR agonist. Compound 1 showed a highly selective M4 mAChR agonistic activity with weak hERG inhibition in vitro. A pharmacokinetic study of compound 1 in vivo revealed good bioavailability and brain penetration in rats. Compound 1 reversed methamphetamine-induced locomotor hyperactivity in rats (1-10 mg/kg, po).
Assuntos
Descoberta de Drogas , Piperidinas/farmacologia , Receptor Muscarínico M4/agonistas , Sulfonamidas/farmacologia , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Metanfetamina/antagonistas & inibidores , Metanfetamina/farmacologia , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Piperidinas/administração & dosagem , Piperidinas/química , Ratos , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/químicaRESUMO
We designed and synthesized novel N-substituted 7-azaindoline derivatives as selective M1 and M4 muscarinic acetylcholine receptors (mAChRs) agonists. Hybridization of compound 2 with the HTS hit compound 5 followed by optimization of the N-substituents of 7-azaindoline led to identification of compound 1, which showed highly selective M1 and M4 mAChRs agonistic activity, weak human ether-a-go-go related gene inhibition, and good bioavailability in multiple animal species.
Assuntos
Descoberta de Drogas , Indóis/farmacologia , Piperidinas/farmacologia , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M4/agonistas , Administração Oral , Animais , Relação Dose-Resposta a Droga , Haplorrinos , Humanos , Indóis/administração & dosagem , Indóis/química , Estrutura Molecular , Piperidinas/administração & dosagem , Piperidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
We designed and synthesized N-substituted 8-azatetrahydroquinolone derivatives as selective M1 and M4 muscarinic acetylcholine receptors agonists. Optimization of selected derivatives led to the discovery of compound 7 as a highly potent M1 and M4 agonist with weak hERG inhibition. Oral administration of compound 7 improved psychosis-like behavior in rats.
Assuntos
Antipsicóticos/farmacologia , Hidroquinonas/síntese química , Hidroquinonas/farmacologia , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M4/agonistas , Administração Oral , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Comportamento Animal/efeitos dos fármacos , Hidroquinonas/química , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Enhancement of serotonergic neurotransmission has been the main stream of treatment for patients with depression. However, delayed therapeutic onset and undesirable side effects are major drawbacks for conventional serotonin reuptake inhibitors. Here, we show that DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant efficacy with minimal undesirable effects, especially nausea and emesis in animal models. DSP-1053 bound human serotonin transporter and 5-HT1A receptor with the K i values of 1.02 ± 0.06 and 5.05 ± 1.07 nmol/L, respectively. This compound inhibited the serotonin transporter with an IC50 value of 2.74 ± 0.41 nmol/L and had an intrinsic activity for 5-HT1A receptors of 70.0 ± 6.3%. In rat microdialysis, DSP-1053, given once at 3 and 10 mg kg(-1), dose-dependently increased extracellular 5-HT levels. In the rat forced swimming test, 2-week administration of DSR-1053 (1 mg kg(-1)) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg(-1)) required 3-week administration to reduce rats immobility time. In olfactory bulbectomy model, 1- and 2-week administration of DSP-1053 reduced both of emotional scores and activity in the open field, whereas paroxetine required 2 weeks to show similar beneficial effects. Although single administration of DSP-1053-induced emesis and vomiting in the rat and Suncus murinus, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes. These results highlight the important role of 5-HT1A receptors in both the efficacy and tolerability of DSP-1053 as a new therapeutic option for the treatment of depression.
RESUMO
Activation of the M1 and M4 muscarinic acetylcholine receptors is thought to play an important role in improving the symptoms of schizophrenia. However, discovery of selective agonists for these receptors has been a challenge, considering the high sequence homology and conservation of the orthosteric acetylcholine binding site among muscarinic acetylcholine receptor subtypes. We report in this study the discovery of novel N-substituted oxindoles as potent muscarinic acetylcholine receptor partial agonists selective for M1 and M4 over M2, M3, and M5. Among these oxindoles, compound 1 showed high selectivity for the M1 and M4 receptors with remarkable penetration into the central nervous system. Compound 1 reversed methamphetamine- and apomorphine-induced psychosis-like behaviors with low potency to extrapyramidical and peripheral side effects.