Evaluation of truncated neuropeptide Y analogues with modifications of the tyrosine residue in position 1 on Y1, Y2 and Y3 receptor sub-types.
Substitutions of the tyrosine residue in position 1 of truncated neuropeptide Y (N-terminal fragment 1-4 linked to C-terminal fragment 18-36 by the epsilon-aminocaproic acid) produced analogues that compete for specific [125I]polypeptide YY (PYY) binding in the frontoparietal cortex (Y1-enriched) with a profile best fitted to a two site-model with KD values in the low and high nM range, respectively. In the hippocampal membrane preparations (Y2-enriched), halogen substitutions on the aromatic ring generated analogues with competition profiles best fitted to a one-site model, revealing differences between the two binding assays and the interaction of these analogues with the Y1 and Y2 receptor sub-types. In the rat vas deferens (Y2-enriched), all truncated analogues inhibited the twitch response with similar or slightly weaker potency than the native molecule. In contrast, these molecules were markedly less potent than neuropeptide Y (NPY) in the rabbit saphenous vein (Y1-enriched) and the rat distal colon (Y3-enriched). Some of the truncated analogues were inactive at up to microM concentrations in the rat distal colon, demonstrating the distinct structural requirement of the receptor sub-type present in this bioassay. These results revealed that amino acid residues between positions 5 and 17 are critical for the maintenance of optimal affinity for the NPY receptors present in the rabbit saphenous vein and the rat distal colon.(ABSTRACT TRUNCATED AT 250 WORDS)
Dumont
Y
Y
Department of Psychiatry, Faculty of Medicine, McGill University, Douglas Hospital Research Center, Verdun, Québec, Canada.
Satoh
H
H
Cadieux
A
A
Taoudi-Benchekroun
M
M
Pheng
L H
LH
St-Pierre
S
S
Fournier
A
A
Quirion
R
R
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009478:Neuropeptide Y / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000378:metabolism*; D012501:Saphenous Vein / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects
D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D014443:Tyrosine