RESUMO
The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5-HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.
Assuntos
Ansiolíticos/síntese química , Antidepressivos/síntese química , Indóis/síntese química , Piridinas/síntese química , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/síntese química , Administração Oral , Animais , Ansiolíticos/química , Ansiolíticos/metabolismo , Ansiolíticos/farmacologia , Antidepressivos/química , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Linhagem Celular , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Modelos Moleculares , Atividade Motora/efeitos dos fármacos , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Receptor 5-HT2A de Serotonina , Receptor 5-HT2B de Serotonina , Receptor 5-HT2C de Serotonina , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are negatively linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1Dbeta and 5-HT1Dalpha, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagonist 4 was structurally modified to produce the selective 5-HT1B receptor inverse agonist 5, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.