RESUMO
The hemagglutinin-tagged human trace amine-associated receptor1 (TAAR1) was stably coexpressed with rat Galpha(s) in the AV12-664 cell line, and receptor activation was measured as the stimulation of cAMP formation. After blockade of endogenously expressed alpha2- and beta-adrenoceptors with 2-[2-(2-methoxy-1,4-benzodioxanyl)]-imidazoline hydrochloride (2-methoxyidazoxan, RX821002) and alprenolol, respectively, the resulting pharmacology was consistent with that of a unique receptor subtype. beta-Phenylethylamine (beta-PEA), the putative endogenous ligand, gave an EC50 of 106 +/- 5 nM in the assay. For a series of beta-PEA analogs used to explore the pharmacophore, small substituents at ring positions 3 and/or 4 generally resulted in compounds having lower potency than beta-PEA, although several were as potent as beta-PEA. However, small substituents at ring position 2 resulted in a number of compounds having potencies as good as or better than beta-PEA. A number of nonselective antagonists known to share affinity for multiple monoaminergic receptors were evaluated for their ability to inhibit beta-PEA stimulation of the human TAAR1. None had an IC50 <10 microM. For comparison, the rat TAAR1 receptor was expressed in the AV12-664 cell line. A number of agonist compounds had significantly different relative potencies between the rat and human TAAR1, demonstrating a significant species difference between the rat and human TAAR1. The TAAR1 receptor exhibits a pharmacologic profile uniquely different from those of classic monoaminergic receptors, consistent with the structural information that places them in a distinct family of receptors. This unique pharmacologic profile suggests the potential for development of TAAR-selective agonists and antagonists to study their physiologic roles.
Assuntos
Receptores Acoplados a Proteínas G/efeitos dos fármacos , Animais , Sequência de Bases , AMP Cíclico/biossíntese , Humanos , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Isoproterenol/farmacologia , Dados de Sequência Molecular , Fenetilaminas/farmacologia , Ratos , Receptores Adrenérgicos alfa 2/fisiologia , Receptores Adrenérgicos beta/fisiologia , Receptores Acoplados a Proteínas G/agonistas , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT1A receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demonstrated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the initial acute activation of 5-HT1A somatodendritic autoreceptors.
Assuntos
Antidepressivos/farmacologia , Piperidinas/farmacologia , Propanóis/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Animais , Antidepressivos/administração & dosagem , Antidepressivos/química , Encéfalo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Técnicas In Vitro , Masculino , Conformação Molecular , Piperidinas/administração & dosagem , Piperidinas/química , Propanóis/administração & dosagem , Propanóis/química , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 1-(1H-indol-4-yloxy)-3-(4-arylpiperidinyl)propan-2-ols possessing potent dual 5-HT(1A) receptor antagonism and serotonin reuptake inhibition was discovered. The fused aryl ring moiety contributed to the robust dual activities irrespective of the regiochemistry associated with its connectivity to the piperidine central ring.
Assuntos
Antidepressivos de Segunda Geração/síntese química , Propanóis/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Antidepressivos de Segunda Geração/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Propanóis/síntese química , Ligação Proteica , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT(1A) receptor antagonism and serotonin reuptake inhibition was discovered. Modification of potential metabolic sites of 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols further improved the in vitro binding affinities and functional antagonism.
Assuntos
Antidepressivos/síntese química , Piperidinas/síntese química , Propanóis/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Indicadores e Reagentes , Conformação Molecular , Estrutura Molecular , Paroxetina/farmacologia , Piperidinas/farmacologia , Propanóis/farmacologia , Relação Estrutura-AtividadeRESUMO
Potent 5-HT1A/SSRIs at low nanomolar and subnanomolar concentrations were identified in a series of 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols. Incorporation of an alpha-Me group in the piperidine ring with its specific stereochemistry enhanced binding affinity at the 5-HT reuptake site and in vitro 5-HT(1A) antagonist functional activity.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Propanóis/síntese química , Propanóis/farmacologia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Indicadores e Reagentes , Paroxetina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT(1A) receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinity at the 5-HT(1A) receptor and serotonin reuptake inhibition at nanomolar concentrations for dual activities.