ISSN:
1573-3904
Keywords:
Conformation
;
Inhibition
;
Peptide ligand
;
Polyamine binding site
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Converging lines of evidence suggest that the N-methyl-D-aspartic acid (NMDA) antagonistproperties of conantokin G (ConG) are mediated through a novel polyamine-associated site.Moreover, structural modification of the heptadecapeptide yields peptides that can eithermimic the NMDA antagonist properties of the parent peptide or produce polyamine-likeactions at NMDA receptors. We synthesized a panel of ConG fragments and evaluated theireffects using a neurochemical assay that predicts pharmacological actions at NMDA receptors.While the C-terminal tetrapeptide elicited a polyamine-like activation of [3H]MK-801 bindingwith a potency comparable to spermine, the N-terminal pentapeptide produced a marginalinhibition of spermine-enhanced [3H]MK-801 binding. These observations suggest that theparent peptide interacts with two distinct sites on NMDA receptors. In contrast, amino acidreplacements in the middle region of ConG resulted in analogues that were of comparable orgreater potency than the parent peptide. The Ala7,Tyr10 derivative is of particular interestsince it is a potent inhibitor (IC50 ∼ 80 nM) of spermine-enhanced [3H]MK-801 binding, andmay thus serve as a precursor for studies designed to 125I-label putative ConG binding sites.Our observations are also consistent with the hypothesis that the termini of ConG are essentialfor an interaction with NMDA receptors, while the middle region of this peptide serves as aspacer unit. This hypothesis is consonant with spectroscopic evidence that ConG possessesa central rigid helical backbone with flexible N- and C-terminal regions. Nonetheless, ConGvariants in which the termini were connected with conformationally stabilizedα- or 310-helical spacers grew progressively less potent as NMDA antagonists as the structural stabilityof these peptides increased. Thus, the middle region of ConG appears to possess functionsother than providing conformational stability. These newly synthesized ConG derivatives mayserve as a basis for the design of novel peptidic or peptidomimetic agents.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1008830104111
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