RESUMO
A series of benzylic piperazines (e.g., 4 and 5) attached to an 'address element', the dipeptide H-D-Tic-D-p-Cl-Phe-OH, 3 has been identified as ligands for the melanocortin subtype-4 receptor (MC4R). We describe herein the structure-activity relationship (SAR) studies on the N-terminal residue of the 'address element'. Several novel dipeptides and reduced dipeptides with high MC4R binding affinities and selectivity emerged from this SAR study.
Assuntos
Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Receptor Tipo 4 de Melanocortina/efeitos dos fármacos , Dipeptídeos/química , Ligantes , Estrutura Molecular , Piperazinas/química , Ligação Proteica , Receptor Tipo 4 de Melanocortina/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-d-Tic-d-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (K(i) = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (K(i) = 6600 nM). Sulfonamide 39 (K(i) = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (K(i) = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (K(i) = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.
Assuntos
Piperazinas/síntese química , Receptor Tipo 4 de Melanocortina/agonistas , Animais , Ligação Competitiva , Disponibilidade Biológica , Linhagem Celular , AMP Cíclico/biossíntese , Humanos , Ligantes , Piperazinas/química , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos F344 , Receptor Tipo 4 de Melanocortina/metabolismo , 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.
