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Exploring the Polyamine Regulatory Site of the NMDA Receptor: a Parallel Synthesis Approach
Author(s) -
Berger Michael L.,
Pöhler Thomas,
Schadt Oliver,
Stanger Maximilian,
Rebernik Patrick,
Scholze Petra,
Noe Christian R.
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200470
Subject(s) - chemistry , pharmacophore , spermine , polyamine , nmda receptor , stereochemistry , residue (chemistry) , dipeptide , binding site , amino acid , biochemistry , receptor , enzyme
Abstract The elongated structures of polyamine inverse agonists such as 1,12‐diaminododecane (N12N) and 5‐(4‐aminobutyl)‐2‐thiopheneoctanamine (N4T8N) lend themselves to a combinatorial chemistry approach to explore a potential polyamine pharmacophore at the NMDA receptor. Herein we describe more than 100 new analogues of N4T8N obtained by breaking up the long octanamine arm into a dipeptide chain of equivalent length. Solid‐phase parallel synthesis based on cross‐linked polystyrene and a Wang anchor allowed the low‐scale preparation of four small libraries based on the combination of two amino acid residues (out of Gly, Leu, Phe, Lys, phenylglycine, Tyr, Trp, His, and Arg). The obtained compounds were tested as modulators of [ 3 H]MK‐801 binding to rat brain membranes and of NMDA‐induced currents in cultured rat hippocampal neurons. Compounds with two aromatic residues acted as binding inhibitors (inverse agonists). Compounds with two Lys residues acted as binding stimulators (agonists) and had stimulatory and inhibitory effects on NMDA‐induced currents, depending on the holding potential. High sensitivity of binding inhibition to spermine was conferred by a Tyr residue, whereas a His residue favored high potency at acidic pH.