Superactive lipophilic peptides discriminate multiple vasoactive intestinal peptide receptors.
To distinguish vasoactive intestinal peptide (VIP) receptors in the brain-mediating neurotransmission and neurotrophism, potent VIP analogues were designed. Using a single amino acid substitution and the addition of a fatty acyl moiety, an analogue was devised that exhibited both a 100-fold greater potency than VIP and specificity for a VIP receptor associated with neuronal survival. This VIP agonist increased neuronal survival via a cAMP-independent mechanism. Identical chemical modification of a prototype VIP antagonist (Met-Hybrid, Neurotensin6-11-VIP7-28) also resulted in a 100-fold greater potency in blocking VIP-mediated increases in neuronal survival. Blockade of circadian activity rhythms was limited to VIP antagonists that could inhibit VIP-mediated increases in cAMP. These lipophilic peptides provide novel tools in receptor discrimination and drug design.
Gozes
I
I
Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel.
Lilling
G
G
Glazer
R
R
Ticher
A
A
Ashkenazi
I E
IE
Davidson
A
A
Rubinraut
S
S
Fridkin
M
M
Brenneman
D E
DE
D000595:Amino Acid Sequence; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018005:Receptors, Vasoactive Intestinal Peptide / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects; D013329:Structure-Activity Relationship; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives / Q000494:pharmacology*
D018005:Receptors, Vasoactive Intestinal Peptide; D014660:Vasoactive Intestinal Peptide