RESUMO
Linear pentapeptides (Penta-cis-Apc-DPhe-Arg-Trp-Gly-NH2) containing 1-amino-4-phenylcyclohexane-1-carboxylic acid (cis-Apc) and substituted Apc are potent hMC4R agonists and they are inactive or weakly active in hMC1R, hMC3R, and hMC5R agonist assays. This study, together with our earlier report on 5-BrAtc, demonstrated the importance of replacing His6 with phenyl-containing rigid templates in achieving good hMC4R agonist potency and selectivity against hMC1R in linear pentapeptides.
Assuntos
Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Cicloexanos/química , Cicloexanos/farmacologia , Receptor Tipo 1 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/agonistas , Sequência de Aminoácidos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Sensibilidade e Especificidade , Especificidade por SubstratoRESUMO
A series of MT-II related cyclic peptides, based on potent but non-selective hMC4R agonist (Penta-c[Asp-His(6)-DPhe(7)-Arg(8)-Trp(9)-Lys]-NH(2)) was prepared in which His(6) residue was systematically substituted. Two of the most interesting peptides identified in this study are Penta-c[Asp-5-ClAtc-DPhe-Arg-Trp-Lys]-NH(2) and Penta-c[Asp-5-ClAtc-DPhe-Cit-Trp-Lys]-NH(2) which are potent hMC4R agonists and are either inactive or weak partial agonists (not tested for their antagonist activities) in hMC1R, hMC3R and hMC5R agonist assays.
Assuntos
Histidina/química , Receptores da Corticotropina/agonistas , Substituição de Aminoácidos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Receptor Tipo 4 de Melanocortina , Receptores de Melanocortina , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Systematic substitution of His(6) residue using non-selective hMC4R pentapeptide agonist (Bu-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2)) as the template led to the identification of Bu-Atc(6)(2-aminotetraline-2-carboxylic acid)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) which showed moderate selectivity towards hMC4R over hMC1R. Further SAR studies resulted in the discovery of Penta-5-BrAtc(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) and Penta-5-Me(2)NAtc(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) which are potent hMC4R agonists and are inactive in hMC1R, hMC3R and hMC5R agonist assays.
