RESUMO
Investigation of L-alanine and D-amino acid replacement of orexin-B revealed that three L-leucine residues at the positions of 11, 14, and 15 in orexin-B were important to show selectivity for the orexin-2 receptor (OX(2)) over the orexin-1 receptor (OX(1)). L-Alanine substitution at position 11 and D-leucine substitution at positions 14 and 15 maintained the potency of orexin-B to mobilize [Ca(2+)](i) in CHO cells expressing the OX(2), while their potency for the OX(1) was significantly reduced. In combined substitutions, we identified that [Ala(11), D-Leu(15)]orexin-B showed a 400-fold selectivity for the OX(2) (EC(50)=0.13nM) over OX(1) (EC(50)=52nM). [Ala(11), D-Leu(15)]orexin-B is a beneficial tool for addressing the functional roles of the OX(2).
Assuntos
Neuropeptídeos/síntese química , Receptores de Neuropeptídeos/agonistas , Substituição de Aminoácidos , Animais , Células CHO , Sinalização do Cálcio/efeitos dos fármacos , Cricetinae , Desenho de Fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neuropeptídeos/química , Neuropeptídeos/farmacologia , Receptores de Orexina , Orexinas , Estrutura Secundária de Proteína , Ratos , Receptores Acoplados a Proteínas G , Receptores de Neuropeptídeos/metabolismoRESUMO
Replacement of the thiol groups in 1, a potent and highly selective Candida albicans GGTase I inhibitor discovered through screening, with an imidazole ring was achieved by using solid phase synthesis. A non-thiol compound, 7, was found as a representative of a new class of potent C. albicans GGTase I inhibitor with high selectivity against human GGTase I.
