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SARs at the NMDA receptor complex

The glycine co-agonist site

: Rader's chem4kids.com

The discovery of glycine as co-agonist at the NMDA receptor complex (NRC) by Johnson & Ascher (1987, Nature 325: 529) is one of the most perplexing highlights of neuroscience research. As another surprise Hashimoto et al. found out that D-serine makes up for about 1/3 of the mammalian brain's serine (1993, J. Neurochem. 60: 783); this quite unusual amino acid acts at the glycine site of the NRC as potently as glycine itself. In cooperation with Christian Noe (Pharmaceutical Chemistry, University Vienna) and the Pharmaceutical Company E. Merck (Darmstadt) many new compounds were synthesized and tested at this binding site.

Berger (1995) J Pharmacol Toxicol Meth 34:79 pdf
Berger et al (1996) Arch Pharm Pharm Med Chem 329:121
Buchstaller et al (2006) J Med Chem 49:864 pdf

: Amino acid residues involved in PA-stimulation of the NRC (from Berger & Noe 2003).

The polyamine regulatory site

Although also discovered more than 20 years ago (Ransom & Stec 1988, J. Neurochem. 51: 830), the modulation of the NRC by polyamines (PAs) has attracted only moderate interest, probably because the endogenous PAs spermidine and spermine are better known for their important role in the nucleus during DNA duplication. However, both of them powerfully increase opening frequency and conductance of the ion channel associated with the NRC. Modulation by PAs is also related to modulation by H⁺, Zn²⁺ and by Ifenprodil. In cooperation with several organic synthesis labs, we have tested a great number of compounds as negative and positive modulators at this site.

Berger et al (1992) Neurosci Lett 142:85
Berger et al (1996) Neurosci Lett 203:25
Donkor & Berger (1997) Bioorg Med Chem Lett 7:1455
Berger et al (1998) Eur J Med Chem 33:3 pdf
Berger & Rebernik (1999) J Pharmacol Exp Ther 289:1584 pdf
Berger (2000) Neurosci Lett 296:29 pdf
Berger & Noe (2003) Curr Top Med Chem 3:51 pdf
Berger et al (2006) Bioorg Med Chem Lett 16:2837 pdf
Pöhler et al (2007) Eur J Med Chem 42:175 pdf