Alpha-helical small molecular size analogues of neuropeptide Y: structure-activity relationships.
C-terminal analogues of neuropeptide Y (NPY) of small molecular size have been synthesized. The influence of chain length, single or multiple amino acid substitution, and segment substitutions on receptor binding, pre- and postsynaptic biological activity, and conformational properties have been investigated. Receptor binding and in vivo assays revealed biological activity for NPY Ac-25-36 that increased with increasing alpha-helicity. In attempts to stabilize the alpha-helical content, three independent types of modified NPY Ac-25-36 analogues were synthesized. Strong agonistic activities could be detected in a series of discontinuous analogues, which are constructs of N-terminal parts linked via different spacer molecules to C-terminal segments. One of the most active molecules was NPY 1-4-Aca-25-36 (Aca, epsilon-aminocaproic acid). For the first time conformational properties of a series of small NPY analogues have been investigated by CD, and correlated with biological activity and receptor binding. A C-terminal dodecapeptide segment of NPY with an amount of 50% substitution to the native C-terminal sequence of NPY was found to exhibit significant receptor binding.
Jung
G
G
Institut für Organische Chemie, Universität Tübingen, Germany.
Beck-Sickinger
A G
AG
Dürr
H
H
Gaida
W
W
Schnorrenberg
G
G
D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002942:Circular Dichroism; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D017476:Receptors, Neuropeptide Y; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D013329:Structure-Activity Relationship
D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D017981:Receptors, Neurotransmitter