RESUMO
Our efforts to optimize prototype opioid receptor-like 1 (ORL1) antagonist 1 led to the discovery of 4-{3-[(2R)-2,3-dihydroxypropyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-[(1S,3S,4R)-spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidine 10. 10 showed potent ORL1 antagonistic activity, excellent selectivity over other opioid receptors, and in vivo efficacy after oral dosing. Currently clinical trials of 10 are underway.
Assuntos
Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Antagonistas de Entorpecentes , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Benzimidazóis/metabolismo , Benzimidazóis/farmacocinética , Células CHO , Cricetinae , Cricetulus , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Camundongos , Piperidinas/metabolismo , Piperidinas/farmacocinética , Ratos , Receptores Opioides/metabolismo , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
We succeeded in cloning the rhesus monkey nociceptin/orphanin FQ peptide (NOP) receptor. The nucleotide sequence and amino acid sequence of the rhesus monkey NOP receptor were 95.9% and 97.8%, respectively, identical to the human NOP receptor. There was no significant difference between the rhesus monkey NOP receptor and the human NOP receptor in the binding affinity of [(125)I] [Thy(14)]nociceptin and the binding of [(35)S]guanosine 5'-O-(gamma thio)triphospate ([(35)S]GTPgammaS) stimulated by nociceptin/orphanin FQ (N/OFQ). A selective NOP receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one ((+)-J-113397) inhibited the [(35)S]GTPgammaS binding activated by N/OFQ using the membrane of the rhesus monkey NOP receptor. The antagonistic activity of (+)-J-113397 to the rhesus monkey NOP receptor was comparable to that to the human NOP receptor. Thus, N/OFQ acts via activation of the NOP receptor in both human and rhesus monkeys without significant species differences.
Assuntos
Benzimidazóis/farmacologia , Peptídeos Opioides/metabolismo , Piperidinas/farmacologia , Receptores Opioides/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Ligação Competitiva , Células CHO , Clonagem Molecular , Cricetinae , Cricetulus , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Macaca mulatta , Dados de Sequência Molecular , Antagonistas de Entorpecentes , Receptores Opioides/metabolismo , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido Nucleico , Receptor de Nociceptina , NociceptinaRESUMO
A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5 H-cyclohepta[ b]pyridine-9-ol ( (-)-8b), a potent and selective opioid receptor-like 1 (ORL1) antagonist, was prepared and evaluated using structure-activity relationship studies with the aim of removing its affinity to human ether-a-go-go related gene (hERG) K (+) channel. From these studies, 10l was identified as an optimized structure with respect to ORL1 antagonist activity, and affinity to the hERG K (+)channel. Furthermore, 10l showed good in vivo antagonism with a wide therapeutic index in regards to adverse cardiovascular effects.