Conformation-activity correlations for chemotactic tripeptide analogs incorporating dialkyl residues with linear and cyclic alkyl sidechains at position 2.
Five stereochemically constrained analogs of the chemotactic tripeptide incorporating 1-aminocycloalkane-1-carboxylic acid (Ac(n)c) and alpha,alpha-dialkylglycines (Deg, diethylglycine; Dpg, n,n-dipropylglycine and Dbg, n,n-dibutylglycine) at position 2 have been synthesized. NMR studies of peptides For-Met-Xxx-Phe-OMe (Xxx=Ac(7)c, I; Ac(8)c, II; Deg, III; Dpg, IV and Dbg, V; For, formyl) establish that peptides with cycloalkyl residues, I and II, adopt folded beta-turn conformations in CDCl3 and (CD3)2SO. In contrast, analogs with linear alkyl sidechains, III-V, favour fully extended (C5) conformations in solution. Peptides I-V exhibit high activity in inducing beta-glucosaminidase release from rabbit neutrophils, with ED50 values ranging from 1.4-8.0 x 10(-11) M. In human neutrophils the Dxg peptides III-V have ED50 values ranging from 2.3 x 10(-8) to 5.9 x 10(-10) M, with the activity order being V > IV > III. While peptides I-IV are less active than the parent, For-Met-Leu-Phe-OH, in stimulating histamine release from human basophils, the Dbg peptide V is appreciably more potent, suggesting its potential utility as a probe for formyl peptide receptors.
Prasad
S
S
Molecular Biophysics Unit, Indian Institute of Science, Bangalore.
Rao
R B
RB
Bergstrand
H
H
Lundquist
B
B
Becker
E L
EL
Balaram
P
P
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006596:Hexosaminidases / Q000187:drug effects / Q000378:metabolism*; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D009842:Oligopeptides; D006596:Hexosaminidases