The effects of selective amino acid substitution upon neuropeptide Y antisecretory potency in rat jejunum mucosa.
The antisecretory potency of NPY and a series of truncated and structural analogues of NPY have been tested upon mucosal preparations of rat small intestine. Single amino acid substitutions, i.e., [Ile34]NPY, [Pro34]NPY, resulted in severe attenuation and loss of biological activity, respectively, and neither peptide affected NPY responses. An agonist order of potency: NPY greater than or equal to [Glu16,Ser18,Ala22,Leu28,31]NPY (ESALL-NPY) greater than [Cys2,Aoc5-24,DCys27]NPY (C2-NPY) greater than [Aoc5-24]NPY greater than [Des-Ser3,Des- Lys4]C2-NPY much greater than [Cys5,Aoc7-20,DCys24]NPY (C5-NPY) greater than equal to [DCys7,Aoc8-17, Cys20]NPY (C7-NPY) greater than [Aoc8-17]NPY greater than or equal to [Ile34]C7-NPY much greater than [Aoc2-27]NPY much greater than [Pro34]C2-NPY was obtained. The use of analogues based upon the tertiary structural model of NPY with varying amounts of N- and C-terminal helical regions removed and replaced with a single 8-aminooctanoic acid residue (Aoc) has allowed us to assess the structural requirements for activation of the regions in close apposition to each other. The polyproline helix, beta-turn and majority of the amphipathic alpha-helix serve a structural role bringing N- and C-terminal residues together for optimal receptor recognition and activation.
Cox
H M
HM
Department of Pharmacology, University of Cambridge, United Kingdom.
Krstenansky
J L
JL
D000595:Amino Acid Sequence; D000818:Animals; D004594:Electrophysiology; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007583:Jejunum / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D009478:Neuropeptide Y