Identification of high-potency neuropeptide Y analogues through systematic lactamization

J Med Chem. 1997 Jan 17;40(2):210-5. doi: 10.1021/jm960593h.


In the pursuit of potent analogues of neuropeptide Y (NPY) that are selective for the Y1 receptor subtype, two lactam bridge scans of a centrally truncated parent compound were synthesized. A single lactam bridge (gamma-carboxyl of Glu to epsilon-amino of Lys) extending from residues i to i + 3 or i to i + 4 of the proposed alpha-helical region (residues 25-31 of NPY) was introduced in des-AA7-24[Gly6]NPY. Cyclogues (contraction of cyclic analogues), which were approximately one-half the size of native NPY, were initially screened for binding affinity at two discrete NPY receptor types using human neuroblastoma cell membranes, SK-N-MC and SK-N-BE2. Exploitation of the subtle differences present on each receptor type allowed for the identification of cyclogues which bound specifically to Y1 receptors with increased affinity when compared to the corresponding linear parent analogue, while one short Y1 specific cyclogue, des-AA2,3,5,7-24cyclo-(26/29)[Gly6,Glu26,Lys2 9,Pro34]NPY, bound with Ki = 16 nM. Other cyclogues showed distinct preference for Y2 receptors and bound in the low-nanomolar range. Functionally, the compounds inhibited the norepinephrine-stimulated accumulation of cAMP indicating that all acted as agonists with varying potencies.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Cell Membrane / metabolism
  • Cell Membrane / ultrastructure
  • Humans
  • Kinetics
  • Lactams / chemistry
  • Lactams / metabolism
  • Molecular Sequence Data
  • Neuroblastoma / metabolism
  • Neuroblastoma / ultrastructure
  • Neuropeptide Y / analogs & derivatives*
  • Neuropeptide Y / chemistry
  • Neuropeptide Y / pharmacology*
  • Receptors, Neuropeptide Y / metabolism


  • Lactams
  • Neuropeptide Y
  • Receptors, Neuropeptide Y
  • neuropeptide Y-Y1 receptor