Development of an orexin-2 receptor selective agonist, [Ala(11), D-Leu(15)]orexin-B

Bioorg Med Chem Lett. 2003 Jan 6;13(1):111-3. doi: 10.1016/s0960-894x(02)00851-x.


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).

MeSH terms

  • Amino Acid Substitution
  • Animals
  • CHO Cells
  • Calcium Signaling / drug effects
  • Cricetinae
  • Drug Design
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides / chemical synthesis*
  • Neuropeptides / chemistry
  • Neuropeptides / pharmacology
  • Orexin Receptors
  • Orexins
  • Protein Structure, Secondary
  • Rats
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide / agonists*
  • Receptors, Neuropeptide / metabolism


  • HCRT protein, human
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexin Receptors
  • Orexins
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide