RESUMO
SAR around a known molecule with dual 5-HT(1D) antagonist and 5-HT(transporter) inhibitory activity has led to the discovery of molecules with improved dual activity and reduced cross-reactivity toward other aminergic receptors (5-HT(1B), alpha(1), and D(2)).
Assuntos
Antidepressivos/farmacologia , Naftalenos/química , Piperazinas/farmacologia , Receptor 5-HT1D de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Animais , Antidepressivos/síntese química , Relação Dose-Resposta a Droga , Cobaias , Cinética , Modelos Químicos , Piperazinas/síntese química , Receptor 5-HT1D de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of compounds combining the naphthylpiperazine and thienopyran scaffolds has been prepared and evaluated for 5-HT reuptake inhibition with 5-HT1D antagonist activity. The design of these compounds has been based on the 'overlapping type' strategy where two pharmacophores are linked in a single molecule. The resultant dual pharmacological profile has the potential to deliver a more efficient treatment for depression.
Assuntos
Piranos/síntese química , Piranos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Animais , Humanos , Piranos/química , Ratos , Antagonistas da Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/químicaRESUMO
The present study investigated the role of the 5-hydroxytryptamine (5-HT, serotonin)1D receptor as a presynaptic autoreceptor in the guinea pig. In keeping with the literature, the 5-HT1B selective antagonist, 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]oxalate (SB224289) potentiated [3H]5-HT outflow from pre-labelled slices of guinea pig cerebral cortex confirming its role as a presynaptic autoreceptor in this species. In addition, the 5-HT1D receptor-preferring antagonists, 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl]-3-pyridin-4-yl-methyl-tetrahydro-pyrimidin-2-one (LY367642), (R)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456219), (S)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456220) and 1-[2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl]-3,3-dimethyl-1,2-dihydro-indol-2-one (LY310762), potentiated [3H]5-HT outflow from this preparation with potencies (EC50 values=31-140 nM) in the same range as their affinities for the guinea pig 5-HT1D receptor (Ki values=100-333 nM). The selective 5-HT1D receptor agonist, R-2-(4-fluoro-phenyl)-2-[1-[3-(5-[1,2,4]triazol-4-yl-1H-indol-3-yl)-propyl]-piperidin-4-ylamino]-ethanol dioxylate (L-772,405), inhibited [3H]5-HT outflow. In microdialysis studies, administration of either SB224289 or LY310762 at 10 mg/kg by the intraperitoneal (i.p.) route, potentiated the increase in extracellular 5-HT concentration produced by a maximally effective dose of the selective serotonin re-uptake inhibitor, fluoxetine (at 20 mg/kg i.p.). In addition, the 5-HT1D receptor-preferring antagonist and 5-HT transporter inhibitor, LY367642 (at 10 mg/kg i.p.), elevated extracellular 5-HT concentrations to a greater extent than a maximally effective dose of fluoxetine. It is concluded that the 5-HT1D receptor, like the 5-HT1B receptor, may be a presynaptic autoreceptor in the guinea pig.
Assuntos
Autorreceptores/fisiologia , Receptores Pré-Sinápticos/fisiologia , Animais , Córtex Cerebral/química , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Cromatografia Líquida de Alta Pressão/métodos , Citalopram/farmacologia , Fluoxetina/farmacologia , Cobaias , Hipotálamo/química , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Indóis/farmacologia , Masculino , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Membrana Transportadoras/farmacologia , Microdiálise/métodos , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Piperidinas/farmacologia , Piperidonas/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Endogâmicos , Receptor 5-HT1B de Serotonina/fisiologia , Receptor 5-HT1D de Serotonina/fisiologia , Serotonina/metabolismo , Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT1 de Serotonina , Proteínas da Membrana Plasmática de Transporte de Serotonina , Especificidade da Espécie , Compostos de Espiro/farmacologia , Frações Subcelulares/química , Frações Subcelulares/patologia , Triazóis/farmacologia , Trítio , Reino UnidoRESUMO
Incorporation of an SRI (serotonin reuptake inhibitor) pharmacophore into a selective 5-HT(1D) agonist has led to the discovery of a molecule having both 5-HT(1D) antagonist and SRI activity. RPS methodology was used to develop the SAR and identify potential approaches to reduce unwanted adrenergic alpha 1 and dopamine D(2) cross-reactivities.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/síntese química , Linhagem Celular , Reações Cruzadas , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Receptor 5-HT1D de Serotonina/metabolismo , Relação Estrutura-AtividadeRESUMO
5-Hydroxytryptamine 3 (5-HT(3)) and alpha 7 nicotinic receptors share high sequence homology and pharmacological cross-reactivity. An assessment of the potential role of alpha 7 receptors in many neurophysiological processes, and hence their therapeutic value, requires the development of selective alpha 7 receptor agonists. We used a recently reported selective alpha 7 receptor agonist, (R)-(-)-5'Phenylspiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)furo[2,3-b]pyridine (PSAB-OFP) and confirmed its activity on human recombinant alpha 7 receptors. However, PSAB-OFP also displayed high affinity binding to 5-HT(3) receptors. To assess the functional activity of PSAB-OFP on 5-HT(3) receptors we studied recombinant human 5-HT(3) receptors expressed in Xenopus oocytes, as well as native mouse 5-HT(3) receptors expressed in N1E-115 neuroblastoma cells, using whole-cell patch clamp and Ca(2+) imaging. Our results show that PSAB-OFP is an equipotent, partial agonist of both alpha 7 and 5-HT(3) receptors. We conclude that it will be necessary to identify the determinant of this overlapping pharmacology in order to develop more selective alpha 7 receptor ligands.